Neuromodulation and associated systems and methods for the management of pain

ABSTRACT

Methods for treating and managing pain in a patient with therapeutic neuromodulation and associated systems and methods are disclosed herein. Chronic or debilitating pain can be associated, for example, with a disease or condition of the abdominal or reproductive viscera. One aspect of the present technology is directed to methods that at least partially inhibit sympathetic neural activity in nerves proximate a target blood vessel of a diseased or damaged organ of a patient experiencing pain. Targeted sympathetic nerve activity can be modulated at least along afferent pathways which can improve a measurable parameter associated with the pain of the patient The modulation can be achieved, for example, using an intravascularly positioned catheter carrying a therapeutic assembly, e.g., a therapeutic assembly configured to use electrically-induced, thermally-induced, and/or chemically-induced approaches to modulate the target sympathetic nerve.

CROSS-REFERENCE TO RELATED APPLICATION(S)

The present application is a continuation of U.S. patent applicationSer. No. 14/379,874, titled “NEUROMODULATION AND ASSOCIATED SYSTEMS ANDMETHODS FOR THE MANAGEMENT OF PAIN,” filed on Aug. 20, 2014, which is a35 U.S.C. § 371 U.S. National Phase application of International PatentApplication No. PCT/US2013/029547, titled “NEUROMODULATION ANDASSOCIATED SYSTEMS AND METHODS FOR MANAGEMENT OF PAIN,” filed on Mar. 7,2013, which claims priority to and the benefit of U.S. ProvisionalPatent Application No. 61/608,579, titled “NEUROMODULATION FORPANCREATIC PAIN MANAGEMENT AND ASSOCIATED SYSTEMS AND METHODS,” filed onMar. 8, 2012, and U.S. Provisional Patent Application No. 61/608,437,titled “TESTICULAR AND/OR PENILE NEUROMODULATION AND ASSOCIATED SYSTEMSAND METHODS,” filed on Mar. 8, 2012, all of which are incorporatedherein by reference in their entireties.

TECHNICAL FIELD

The present technology relates generally to pain management usingneuromodulation and associated systems and methods.

BACKGROUND

Patients with hepatobiliary diseases (e.g., diseases of the liver,gallbladder and biliary tract), conditions of the pancreas (e.g.,chronic pancreatitis, pancreatic cancer), and visceral arteryinsufficiency can all suffer from chronic and/or intractable pain. Suchpain associated with these conditions, for example, can be bothdebilitating and difficult to treat. Typically, analgesics and/ornarcotics are used to manage the patient's pain; however, conventionalpain-management medications (e.g., opiates) are often ineffective oronly partially effective and can cause undesirable side effects anddependency. Conventional non-pharmacological treatments for thetreatment of conditions of the pancreas, for example, can includelocally injecting anesthetic drugs or nerve-destroying agents (e.g.,alcohol) to reduce nerve signaling through the celiac ganglia and/orceliac plexus. This procedure, known as a “celiac plexus block,” can beeffective in some cases, but its effectiveness tends to diminish overtime. For example, the procedure must typically be repeated every threeto four months for sustained pain management. Furthermore, executing aconventional celiac plexus block involves inserting a needle through thegastrointestinal, intraabdominal and/or retroperitoneal anatomy to aposition proximate the celiac plexus. This manner of accessing theceliac plexus can be imprecise and can have a variety of seriouspotential complications, include retroperitoneal hemorrhage, spinal-cordpuncture, and paraplegia. Accordingly, there is a need for alternativetreatments.

Chronic pain can also be associated with both male and femalereproductive/genital organs. For example, orchialgia is a conditioncharacterized by long term testicular pain that often has no knownetiology but can in some cases be caused by injury, infection, surgery,cancer or testicular torsion and can be a possible complication aftervasectomy. Vulvodynia is a condition characterized by chronic painaffecting the vulvar area and often occurs without an identifiable causeor visible pathology. Both orchialgia and vulvodynia are treated, forexample, with anti-inflammatory medications or other pain medications,antidepressants (e.g., nortriptyline, amitriptyline), and anti-anxietydrugs; however, these are not always effective and can have undesirableside effects. Intractable cases of orchialgia can be treated withmicrosurgical denervation of the spermatic cord; however, the procedurehas several potential complications (e.g., testicular atrophy,hydrocele, hypoesthesia of the scrotum, penile shaft, inguinal or medialthigh skin, and persistent testicular pain). Intractable cases ofvulvodynia can be treated with injection or surgical destruction of thepudendal nerve; however, the procedure has several potentialcomplications (e.g., permanent vulva numbness, continued vulvodyniapain, etc.). Accordingly, there is a need for alternative treatments.

Pain signals travel along various neural pathways through the body,including the sympathetic nervous system (SNS). The SNS is a primarilyinvoluntary bodily control system typically associated with stressresponses. Fibers of the SNS extend through tissue in almost every organsystem of the human body. For example, some efferent SNS fibers extendfrom the brain, intertwine along the aorta, and branch out to variousorgans. Likewise, afferent nerve fibers traveling with SNS nerve fiberscan transmit signals, including pain signals, from the organs (e.g.,abdominal organs, reproductive/genital organs) to the brain.

BRIEF DESCRIPTION OF THE DRAWINGS

Many aspects of the present disclosure can be better understood withreference to the following drawings. The components in the drawings arenot necessarily to scale. Instead, emphasis is placed on illustratingclearly the principles of the present disclosure.

FIGS. 1A-1E illustrate various examples of pain scales that can be usedto quantify or qualify pain as it is occurring and in accordance with anembodiment of the present technology.

FIGS. 2A-2B are anatomical views illustrating the abdominal viscera andthe nearby nerve structures and vessels.

FIG. 2C is a partially cross-sectional view illustrating neuromodulationat a treatment location within the superior mesenteric artery inaccordance with an embodiment of the present technology.

FIG. 3A is anatomical views illustrating the testicular artery andnearby organ structures and vessels.

FIG. 3B is a partially cross-sectional view illustrating neuromodulationat a treatment location within the testicular artery in accordance withan embodiment of the present technology.

FIG. 4 is a cross-sectional anatomical view illustrating a common iliacartery, an internal iliac artery, an external iliac artery, an internalpudendal artery, a superior gluteal artery and other nearby structuresand vessels.

FIG. 5 is an anatomical view illustrating a portion of the uterus,vagina, an ovary and nearby organs and vessels.

FIGS. 6A and 6B are anatomic views of the arterial vasculature andvenous vasculature, respectively, of a human.

FIG. 7 illustrates an intravascular neuromodulation system configured inaccordance with an embodiment of the present technology.

FIG. 8 is a block diagram illustrating a method of modulating targetsympathetic nerves in accordance with an embodiment of the presenttechnology.

FIG. 9 is a conceptual illustration of the sympathetic nervous system(SNS) and how the brain communicates with the body via the SNS.

DETAILED DESCRIPTION

The present technology is generally directed to modulation of one ormore nerve structures associated with abdominal viscera (e.g., stomach,intestine, liver and biliary system, pancreas, spleen, kidneys, ureters,and suprarenal glands) and/or reproductive organs to reduce perceivedpain associated with conditions or diseases of these physiologicalstructures. For example, several embodiments are directed to modulationof at least a portion of the superior mesenteric plexus, the celiacplexus, and/or the hepatic plexus to reduce pain associated withconditions of the pancreas, the liver or other abdominal organ systems.Other embodiments are directed to modulation of sympathetic nervesinnervating male and female reproductive/genital organs to reduceperceived chronic pain associated with conditions or diseases associatedwith the testes (e.g., orchialgia) and/or penis (e.g., injury,Peyronie's disease) as well as the vulva, vagina, and/or clitoris toreduce perceived chronic pain associated with conditions or diseasesassociated with the female reproductive system (e.g., vulvodynia). Forexample, some embodiments are directed to modulation of at least aportion of the testicular and/or penile sympathetic nerves (e.g.,sympathetic nerves along the testicular vessels, pudendal vessels orother associated structures), and/or to modulation of at least a portionof the spermatic plexus, the lumbar plexus, the sacral plexus, theuterovaginal plexus and/or particular sympathetic nerves innervating thetestes, penis, vulva, vagina, and/or clitoris (e.g., perineal nerve,ilioinguinal nerve, genitofemoral nerve, pudendal nerve).

In many embodiments, modulation of targeted nerves and nerve structurescan include modulation of the nerves in locations proximate (e.g., at ornear) a percutaneously accessible artery (e.g., superior mesentericartery, the celiac artery) or vein (e.g., superior mesenteric vein)and/or other suitable structures. As discussed in greater detail below,neuromodulation of one or more nerve structures associated with theabdominal organs (e.g., pancreas, liver, gallbladder) or associated withreproductive organs (e.g., testes, penis, vulva, vagina, uterus,ovaries, etc.) can include rendering neural fibers inert, inactive, orotherwise completely or partially reduced in function. This result canbe electrically-induced, thermally-induced, or induced by anothermechanism (e.g., chemically-induced) during a neuromodulation procedure,e.g., a procedure including percutaneous transluminal intravascularaccess.

Specific details of several embodiments of the technology are describedbelow with reference to FIGS. 1A-9. The embodiments can include, forexample, modulating nerves proximate (e.g., at or near) the superiormesenteric artery, the inferior mesenteric artery, the celiac artery orone of its branches, the superior mesenteric vein, the internal pudendalartery, a testicular artery and/or other suitable structures. Althoughmany of the embodiments are described herein with respect toelectrically-induced, thermally-induced, and chemically-inducedapproaches, other treatment modalities in addition to those describedherein are within the scope of the present technology. Additionally,other embodiments of the present technology can have differentconfigurations, components, or procedures than those described herein. Aperson of ordinary skill in the art, therefore, will accordinglyunderstand that the technology can have other embodiments withadditional elements and that the technology can have other embodimentswithout several of the features shown and described below with referenceto FIGS. 1A-9′.

As used herein, the terms “distal” and “proximal” define a position ordirection with respect to the treating clinician or clinician's controldevice (e.g., a handle assembly). “Distal” or “distally” can refer to aposition distant from or in a direction away from the clinician orclinician's control device. “Proximal” and “proximally” can refer to aposition near or in a direction toward the clinician or clinician'scontrol device.

I. CHRONIC PAIN

Nociceptive pain (e.g., caused by activation of nociceptors) can beconsidered chronic if it extends beyond an expected healing duration.Chronic pain originating in the viscera (organs) can be localized, butoften can be difficult to locate as several visceral regions produce“referred” pain when damaged or inflamed (e.g., where sensation islocated in an area distant from the site of pathology or injury). Inaddition to reduced quality of life and discomfort, chronic pain ofvarying etiologies can affect brain structure and function. For example,magnetic resonance imaging studies have shown abnormal anatomical andfunctional connectivity in areas of the brain relating to painprocessing and persistent pain has been shown to cause grey matter loss,which is reversible once pain is resolved. Additionally brain activityin patients suffering from chronic pain (e.g., measured byelectroencephalogram) has been demonstrated to be altered, suggestingpoint-induced neuroplastic changes. Chronic pain is associated withhigher rates of depression, anxiety, sleep disturbance and insomnia dueto medications and underlying disease symptoms.

Pharmacologic management of pain is commonly used to alleviate bothdiscomfort and other sequelae of chronic pain, particularly chronic painassociated with conditions and diseases of the abdominal viscera (e.g.,pancreas, gallbladder, liver, stomach, intestines, etc.) and thereproductive system (e.g., testes, vulva, etc.). Pain medication caninclude, for example, analgesia (e.g., acetaminophen, salicylic acid,non-steroidal anti-inflammatory drugs, opioids, COX-2 inhibitors) aloneor in combination with other agents (e.g., anesthetics, antidepressants,antiepileptics, narcotics, etc.).

For some conditions, specialized procedures are used to treat pain, suchas administering nerve blocks or microsurgical techniques to damage orocclude nerves. For example, a celiac ganglia/plexus nerve blockingprocedure includes guided injections, e.g., of drugs (e.g. steroids,anesthetics), or nerve-destroying (e.g. alcohol), or nerve-blocking(e.g. onabotulinumioxinA) agents, to reduce nerve signaling through theceliac ganglia/plexus for the treatment of intractable pain fromcancers, such as pancreatic cancer, or from chronic pancreatitis. Accessto the celiac nerves via (1) X-ray computed tomography (CT) guidedneedle through the skin or (2) endoscopic catheters delivered throughthe gastrointestinal tract can be used to deliver combination oflong-acting anesthetics, steroids, or onabotulinumtoxinA (sold under thetrademark BOTOX), or to deliver alcohol or other neutrally destructiveagents for destroying nerve fibers.

Nerve blocking and microsurgical techniques appear to be able toalleviate pain for 3-4 month durations in some patients; however, thetechniques have limited efficacy, and can pose undesirable risks (e.g.,paraplegia, damage to nearby structures, etc.). Prescribed painmedication therapies are also limited in their efficacy as they areoften not able to control pain in the setting of hepatobiliary diseases,chronic pancreatitis, pancreatic cancer, and visceral arteryinsufficiency, as well as in some conditions of the reproductive organs,such as orchialgia and vulvodynia.

A patient suspected of having chronic, debilitating or intractable painor having one or more positive diagnosis of a condition or diseaseassociated with chronic pain, can be evaluated for pain level and levelof function. Pain evaluation can include capturing features such asquality (e.g., burning, cramping, aching, deep, superficial, boring,shooting, etc.), severity, location, radiation pattern, duration, timing(e.g., including pattern and degree of fluctuation and frequency ofremissions), and exacerbating and relieving factors. Additionally, painevaluation can also assess aspects of pain relating to a patient's levelof functioning, for example, by focusing on activities of daily living(e.g., dressing, bathing), employment, avocations, and personalrelationships (e.g., sexual activity/ability). Use of pain measurementscales can assist in the evaluation process by measuring a patient'spain intensity and/or functionality, for example. Pain scales, as wellas other data that can be collected in a pain evaluation of a patient,are based on self-report, observational (behavioral), or physiologicaldata. Self-report is considered the primary form and common forchildren, adolescents, adults and seniors who are able to communicate;however, additional pain scales are also available for neonates,infants, and other persons whose communication is impaired. FIGS. 1A-1Eillustrate various examples of pain scales that can be used to quantifypain as it is occurring. For example, an adult patient can be assessedusing a standardized Visual Analog Scale (VAS) where patients areinstructed to mark a line anchored with terms describing the extremes ofpain intensity (FIG. 1A). Operationally, the VAS is usually a horizontalline, 100 mm in length, anchored by word descriptors at each end. Thepatient marks on the line the point that they feel represents theirperception of their current state. The VAS score is determined bymeasuring in millimeters from the left hand end of the line to the pointthat the patient marks. The position of the patient's marking is thentranslated into a score from 1 to 10. Other types of pain scales forchildren might include a graphic faces pain scale, Wong-Baker FACES PainRating Scale (FIG. 1B), a colored analogue scale, or an observationalscale such as a Face Legs Arms Cry Consolability Scale (FLACC). Othertypes of scales, such as a word descriptor scale (FIG. 1C), a verbalscale (FIG. 1D) and a Functional pain scale (FIG. 1E) can also be usedalone or in conjunction with other pain measurement scales or assessmenttools to quantify pain.

A. Conditions and Diseases of the Abdominal Viscera

The abdominal viscera can include, for example, the stomach, intestine,liver and biliary system, pancreas, spleen, kidneys, ureters, andsuprarenal glands. Several embodiments described herein address chronicand/or otherwise intractable pain associated with conditions or diseasesof these abdominal organs. For example, pain associated with conditionsof the pancreas (e.g., pancreatic cancer and pancreatitis) can bedebilitating and difficult to treat. Pancreatic cancer is characterizedby malignant tumors (e.g., adenocarcinomas) within the pancreas.Pancreatic cancer is commonly diagnosed at late stage in patients afterpresentation of symptoms such as abdominal pain, lower back pain and/orjaundice. Prognosis is poor and pain management is typically necessaryfor pancreatic cancer patients to improve quality and life expectancy.Pancreatitis is the inflammation of the pancreas that occurs whenpancreatic enzymes (e.g., trypsin) that digest food are activated in thepancreas instead of the small intestine. Pancreatitis can be acute(e.g., begin suddenly and last a few days or weeks) or chronic (e.g.,occur over many years). The most common symptoms of pancreatitis areupper abdominal burning pain radiating to the back, nausea and vomitingthat worsens with eating. Chronic pancreatitis can lead to diabetes orpancreatic cancer. Diagnosis is based on characteristic abdominal painthat can be severe, elevated blood amylase or lipase levels, andabdominal ultrasound. Pain management (e.g., with the use of analgesics)along with dehydration control are the primary treatments, with chronicpancreatitis requiring long-time use of pain medications, includingopiates (e.g., morphine).

Hepatobiliary diseases affect the liver and/or biliary tract and caninclude, for example, hepatitis, other infectious diseases (e.g.,toxoplasmosis, syphilis, Epstein-Barr virus, yellow fever, rubella,leptospirosis, etc.), alcoholic liver disease, toxic liver disease,fatty liver disease, liver tumors, meabolic diseases (e.g.,henochromaosis, Gilbert's syndrome, etc.), vascular disorders (e.g.,Budd-Chiari syndrome), liver abscess or cysts, malignant neoplasm of thegallbladder or other parts of the biliary tract, gallstones,cholecystitis, and gallbladder obstructions among other conditions. Manyof these conditions and diseases are associated with pain, particularlyintractable abdominal pain requiring pain management treatment withanalgesics.

In addition to the above conditions and diseases of the abdominalviscera, other abdominal organs or structures can also be associatedwith chronic pain, such as, for example, conditions of the spleen (e.g.,inflammation, enlarged spleen due to mononucleosis, leukemia, lymphoma,Hodgkin's disease, etc.) and stomach (e.g., cancer), and the smallintestine and colon (e.g., cancer, untreatable chronic ischemia). Inother embodiments, patients can also suffer from chronic pain associatedwith, for example, diseases and conditions associated with theperipheral vasculature (e.g., ischemia, claudication), complex regionalpain syndrome (e.g., reflex sympathetic dystrophy), Raynaud's syndrome,and scleroderma.

B. Conditions and Diseases of the Reproductive System and Pelvic Region

The male reproductive system includes the reproductive organs necessaryfor sperm production and storage (e.g., testes, scrotum, andepididymis), ejaculatory fluid producing glands (e.g., seminal vesicles,prostate, and vas deferens), and reproductive organs used for copulationand deposition of sperm (e.g., penis, urethra, vas deferens, andCowper's gland). Several embodiments described herein address chronicand/or otherwise intractable pain associated with conditions or diseasesof these male reproductive organs. For example, orchialgia is acondition characterized by long term testicular pain caused by injury,infection, surgery, cancer or testicular torsion and can be a possiblecomplication after vasectomy. Orchialgia is treated, for example, withNSAIDs or other pain medications; however, these are not alwayseffective and can have undesirable side effects. Intractable cases oforchialgia can be treated with microsurgical denervation of thespermatic cord; however, the procedure has several potentialcomplications (e.g., testicular atrophy, hydrocele, hypoesthesia of thescrotum, penile shaft, inguinal or medial thigh skin, and persistenttesticular pain). Varicocele is an abnormal enlargement of thepampiniform venous plexus in the scrotum which can cause a dragging-likeor aching pain within the scrotum.

The female reproductive system includes the uterus which hostsdeveloping fetuses, produces vaginal and uterine secretions and providesa path for male sperm to the fallopian tubes, and includes the ovarieswhich produce the eggs. The uterus connects to the external genitalia(e.g., the labia, clitoris and urethra) through the vagina which isattached to the uterus through the cervix. Several embodiments describedherein address chronic and/or otherwise intractable pain associated withconditions or diseases of these female reproductive organs andgenitalia. For example, vulvodynia is a condition characterized bychronic pain affecting the vulvar area and often occurs without anidentifiable cause or visible pathology. Possible causes of vulvodyniacan be inflammation, allergy, autoimmune disorder, infection, injury andneuropathy (e.g., including an increased number of nerve ending is thevaginal area), results of genital surgery or pelvic floor dysfunction.In many cases, specific causes of vulvodynia are often elusive; however,pain is the most notable symptom and can be characterized as a burning,stinging, irritation or sharp pain that occurs in the vulva, includingthe labia and the entrance to the vagina. Vulvar Vestibulitis Syndrome(VVS) is vulvodynia located to the vestibular region, while clitorodyniais pain that extends into the clitoris. Vulvodynia is often treated, forexample, with topical creams and gels including estrogen and/ortestosterone, antidepressants (e.g., nortriptyline, amitriptyline), andanti-anxiety drugs; and injectable medications including anesthetics,estrogens, or systemic or local steroids. For example, cortisone andlocal anaesthetic can be injected where the pudendal nerve is identifiedin its canal; however, these are not always effective and can haveundesirable side effects. Intractable cases of vulvodynia can be treatedwith injection or surgical destruction of the pudendal nerve; however,the procedure has several potential complications (e.g., permanent vulvanumbness, continued vulvodynia pain, etc.).

In another example, vaginismus is an involuntary spasm of the muscles(e.g., a reflex of the pubococcygeus muscle) surrounding the vagina.Vaginismus is characterized by spasms that close the vagina makingvaginal penetration during sex difficult, painful or impossible. Incases that are determined to be physically manifested, clinicians havetreated female patients having vaginismus with onabotulinumtoxinA (soldunder the trademark BOTOX) to relax the muscles around the vagina toassist in penetration. However, this is not always effective, can haveundesirable side effects and the treatments have limited duration (e.g.,4 months). Pain with sexual intercourse, known as dyspareunia, can beanother manifestation of excess pain signal transmission from the pelvicfloor, vagina, surgical sites, and/or cervix.

Other sources of pelvic pain can be derived from nerve disorders such asplexopathy. For example, a sacral and/or lumbosacral plexopathy is adisorder affecting the sympathetic nerves of the lumbosacral plexus(e.g., the anterior divisions of the lumbar nerves, sacral nerves, andcoccygeal nerve), which can be caused by trauma, nerve compression,vascular disease, metabolic disease (e.g., diabetes), or infection.Symptoms associated with a plexopathy include pain, loss of motorcontrol and sensory deficits among others. Mild cases can be treatedwith short or long-term administration of analgesia and/or musclerelaxers. More severe cases can require additional treatments such assurgical decompression of the nerve plexus center or other neurovascularsurgical intervention to address the pain.

II. NEUROMODULATION FOR TREATMENT OF PAIN

A. Neuromodulation of the Celiac Plexus and/or the Celiac Ganglia

The celiac plexus is a complex network of nerves located in the abdomen,where the celiac artery, superior mesenteric artery, and renal arteriesbranch from the abdominal aorta. The celiac plexus is located caudal tothe diaphragm (in an antecrural position), surrounds the origin of theceliac trunk, and comprises a dense network of ganglia (e.g., celiacganglia) and interconnecting fibers. The celiac plexus includes a numberof smaller plexuses, such as the hepatic plexus, splenic plexus, gastricplexus, pancreatic plexus and suprarenal plexus. The celiac plexus isknown to transmit pain sensation originating from the pancreas as wellas most of the abdominal viscera with the exception of the colon, rectumand pelvic organs (Levy et. al. Gastrointestinal Endoscopy Clinics ofNorth America. 2012; 22: 231-47, viii, herein incorporated by referencein its entirety). For example, the neurons that innervate the pancreascan receive nociceptive stimulation and then transmit this paininformation to the celiac plexus, and then to the thalamus and cortex ofthe brain, thereby inducing the sensation of pain. A ganglion is definedas a collection of nerve cell bodies and glial cells that areinterconnected via a sense network of neural rami and septae ofconnective tissue. The celiac ganglia can be detected, for example,using endoscopic ultrasound or other techniques (e.g., CT, fluoroscopy).For example, visualized ganglia are typically located adjacent to theceliac artery, anterior to the aorta, and are predominantly oval oralmond-shaped, ranging in size from 2 to 20 mm.

Neuromodulation of the celiac plexus and/or the celiac ganglia is thepartial or complete incapacitation or other effective disruption orregulation of nerves innervating the pancreas, e.g., nerves terminatingin or originating from the pancreas or in structures closely associatedwith the pancreas) and/or nerves innervating the liver, gallbladder,stomach, spleen, kidney, small intestine, ascending and transverse colonand the ovarian theca, respectively. In particular, neuromodulation ofthe celiac plexus comprises inhibiting, reducing, blocking, pacing,up-regulating, and/or down-regulating neural communication along neuralfibers (e.g., efferent and/or afferent neural fibers) innervating thepancreas, or in other embodiments, innervating the liver, gallbladder,and other abdominal organs. In other embodiments, the treatmentprocedure can target a subset of nerves of a smaller plexus within theceliac plexus, such as the hepatic plexus (e.g., along the hepaticartery), the splenic plexus (e.g., along the splenic artery), thegastric plexus (e.g., along the left gastric artery), and the pancreaticplexus (e.g., along the pancreatic artery). These targets can beintravenously accessed through femoral, brachial or radial approacheswhere a catheter could be navigated through the celiac trunk to thesubsidiary arteries (e.g., hepatic, splenic, pancreatic, etc.). Suchincapacitation, disruption, and/or regulation can be long-term (e.g.,permanent or for periods of months, years, or decades) or short-term(e.g., for periods of minutes, hours, days, or weeks).

Sympathetic neural activity via the nerve fibers of the celiac plexusand/or celiac ganglion, and particularly sympathetic afferent nerves,are responsible for carrying pain signals from the abdominal viscera tothe brain in patients e.g., patients with conditions and diseases of thepancreas, including, but not limited to, acute pancreatitis, chronicpancreatitis, and pancreatic cancer. Neuromodulation of the celiacplexus and/or the celiac ganglia is expected to be useful in reducingperceived pain associated with these conditions, as well as painassociated with hepatobiliary disease and visceral artery insufficiency.Methods and systems for neuromodulation of the celiac plexus and/orceliac ganglia for efficaciously treating and/or reducing painassociated with several clinical conditions of the abdominal viscera aredescribed herein.

Furthermore, afferent sympathetic activity from the abdominal visceracan contribute to central sympathetic tone or drive. Accordingly,neuromodulation of the celiac plexus and/or celiac ganglia is expectedto be useful in treating clinical conditions associated with centralsympathetic activity (e.g., overactivity or hyperactivity), particularlyconditions associated with central sympathetic overstimulation.Conditions associated with central sympathetic activity (e.g.,overactivity or hyperactivity) include, for example, hypertension, heartfailure, acute myocardial infarction, metabolic syndrome, insulinresistance, diabetes, left ventricular hypertrophy, chronic and endstage renal disease, inappropriate fluid retention in heart failure,cardio-renal syndrome, polycystic kidney disease, osteoporosis, andsudden death, among other conditions. Accordingly, in some patients,reducing localized sympathetic drive via the celiac plexus and/or celiacganglia, central sympathetic drive, and/or other benefits fromneuromodulation can outweigh the complete or partial loss ofpancreatic-nerve functionality. Moreover, disrupting efferent and/orafferent nerve traffic to/from the visceral abdominal organs (e.g.,stomach, intestines, liver, pancreas) may conceivably impact hormonalactivity in the abdominal organs and thereby impact conditionsassociated with overfeeding, obesity, insulin resistance, and diabetesamong other conditions. Structures in the abdominal viscera may also beimportant in sequestration of intra and extravascular fluid, anddenervation (e.g., complete or partial) of these organs could therebyalso impact conditions of fluid excess (e.g., heart failure).

B. Neuromodulation of the Superior Mesenteric Plexus and/or the SuperiorMesenteric Ganglion

The superior mesenteric plexus is a continuation of the lower part ofthe celiac plexus. The superior mesenteric plexus surrounds the superiormesenteric artery and divides into a number of secondary plexuses and/orgives rise to sympathetic nerve fibers innervating the pancreas, thesmall intestine, and colon in the abdomen. The superior mesentericganglion is the synapse point for one of the pre- and post-synapticnerves of the sympathetic division of the autonomous nervous system.Specifically, contributions to the superior mesenteric ganglion arisefrom TV10 and TV11, and these nerve fibers go on to innervate the smallintestine, the ascending colon and the transverse colon.

Neuromodulation of the superior mesenteric plexus and/or the superiormesenteric ganglia is the partial or complete incapacitation or othereffective disruption or regulation of nerves innervating the pancreas(e.g., nerves terminating in or originating from the pancreas or instructures closely associated with the pancreas) and/or nervesinnervating the small intestine, and ascending and transverse colon. Inparticular, neuromodulation of the superior mesenteric plexus comprisesinhibiting, reducing, blocking, pacing, up-regulating, and/ordown-regulating neural communication along neural fibers (e.g., efferentand/or afferent neural fibers) innervating the pancreas, or in otherembodiments, innervating the small intestine, and ascending andtransverse colon. Such incapacitation, disruption, and/or regulation canbe long-term (e.g., permanent or for periods of months, years, ordecades) or short-term (e.g., for periods of minutes, hours, days, orweeks).

Similar to the sympathetic neural activity via the nerve fibers of theceliac plexus and/or celiac ganglion, the sympathetic neural activityassociated with the superior mesenteric plexus and/or the superiormesenteric ganglia can be associated with carrying pain signals from theabdominal viscera to the brain in patients e.g., patients withconditions and diseases of the pancreas, including, but not limited to,acute pancreatitis, chronic pancreatitis, and pancreatic cancer.Neuromodulation of the superior mesenteric plexus and/or the superiormesenteric ganglia is expected to be useful in reducing perceived painassociated with these conditions, as well as pain associated with paincausing conditions (e.g., cancer) associated with the small intestineand colon and with visceral artery insufficiency. Also as describedabove, neuromodulation of the superior mesenteric plexus and/or thesuperior mesenteric ganglia is also expected to be useful in treatingclinical conditions associated with central sympathetic activity (e.g.,overactivity or hyperactivity), particularly conditions associated withcentral sympathetic overstimulation. Methods and systems forneuromodulation of the superior mesenteric plexus and/or the superiormesenteric ganglia for efficaciously treating and/or reducing painassociated with several clinical conditions of the abdominal viscera,are further described herein.

C. Neuromodulation of Sympathetic Nerve Fibers Innervating ReproductiveOrgans and the Pelvic Region

1. Sympathetic Nerves Innervating the Testes and Penile Tissue

The spermatic plexus is derived from the renal plexus, and itaccompanies the testicular artery (e.g., internal spermatic artery) toinnervate the testis. Testicular and/or penile sympathetic nerves (e.g.,sympathetic nerves along the testicular vessels, pudendal vessels orother associated structures), innervate portions of the male genitalia.For example, the genitofemoral nerve, which originates from the upperpart of the lumbar plexus, is responsible for both the efferent andafferent (along with the ilioinguinal nerve) limbs of the cremastericreflex where it innervates the cremaster muscle and the scrotal skin.The ilioinguinal nerve accompanies the spermatic cord and supplies thescrotal skin, skin over the root of the penis, groin and medial thigh.The pudendal nerve originates in the sacral plexus and accompanies theinternal pudendal vessels and eventually gives rise to the perinealnerve and the dorsal nerve of the penis in males. The perineal nervewhich sits adjacent and below the internal pudendal artery and becomesthe posterior scrotal nerves in males. The neurons that innervate thetestes, scrotum and penis can receive nociceptive stimulation and thentransmit this pain information to the spermatic plexus, the lumbarplexus, the sacral plexus, etc. and then to the thalamus and cortex ofthe brain, thereby inducing the sensation of pain. To reduce perceivedchronic pain associated with conditions or diseases associated with thetestes (e.g., orchialgia) and/or penis (e.g., injury, Peyronie'sdisease), at least partial neuromodulation of these nerve fibers can beperformed.

2. Sympathetic Nerves Innervating the Vulva, Vagina and/or Clitoris andOther Female Reproductive Structures

Sympathetic nerves derived from the lumbar plexus, the sacral plexus,the uterovaginal plexus and/or particular sympathetic nerves innervatingthe vulva, vagina, and/or clitoris (e.g., perineal nerve, ilioinguinalnerve, genitofemoral nerve, pudendal nerve), can transmit pain signalsassociated with female reproductive organ or genitalia dysfunction tothe brain. For example, the genitofemoral nerve, which originates fromthe upper part of the lumbar plexus, is responsible for both efferentand afferent (along with the ilioinguinal nerve) nerve fibers to theskin covering the mons pubis and the labium majus (e.g., anteriorportion of the vulva which includes the labia majora, and surrounds thestructures of the vulval vestibule such as the labia minora, clitorisand vaginal opening) in females. The pudendal nerve, which originates inthe sacral plexus, gives rise to the perineal nerve and the dorsal nerveof the clitoris in females. For example, the perineal nerve which isadjacent to and below the internal pudendal artery gives rise to theposterior labial nerves in females. The vaginal plexus arises from thelower part of the pelvic plexus (e.g., the inferior hypogastric plexus)which is a plexus of nerves that supplies the viscera of the pelviccavity and accompany the branches of the internal iliac artery (e.g.,vaginal arteries, vaginal venous plexus). The vaginal plexus isdistributed to the walls of the vagina to the erectile tissue of thevestibule and to the clitoris. The uterine plexus accompanies theuterine artery to the side of the uterus between the layers of the broadligament and it communicates with the ovarian plexus. Accordingly, toreduce perceived chronic pain associated with conditions or diseasesassociated with the lumbar plexus, the sacral plexus, the uterovaginalplexus and/or particular sympathetic nerves innervating the vulva,vagina, and/or clitoris, at least partial neuromodulation of these nervefibers can be performed.

3. Other Sympathetic Nerves Innervating the Pelvic Region

Often, the sacral plexus and the lumbar plexus are considered to be onelarge nerve plexus, the lumbosacral plexus. In front of the sacralplexus are the internal iliac artery, internal iliac vein, the ureter,and the sigmoid colon. The superior gluteal artery and vein run betweenthe lumbosacral trunk (e.g., wherein the sacral and lumbar plexusesjoin) and the first sacral nerve, and the inferior gluteal artery andvein run between the second and third sacral nerves. Nociceptivestimulation from the pelvic region, such as due to trauma, nervecompression, vascular disease, infection, or otherwise diagnosed as asacral plexopathy, can be transmitted through the lumbosacral plexus tothe brain. To reduce perceived chronic pain associated with conditionsor diseases associated with sacral plexopathy, at least partialneuromodulation of these nerve fibers can be performed.

4. Aspects of Neuromodulation Sympathetic Nerve Fibers InnervatingReproductive Organs and the Pelvic Region

To address any one of the above conditions or diseases, neuromodulationof the appropriate sympathetic nerves can be performed. For example, thespermatic plexus, the genital branch of the genitofemoral nerve, theilioinguinal nerve, the sacral plexus, the pudendal nerve, the perinealnerve, the vaginal plexus, the uterine plexus and/or the lumbosacralplexus can include the partial or complete incapacitation or othereffective disruption or regulation of nerves innervating the testes,penis, vulva, vagina, clitoris, uterus, and/or other structuresassociated with the pelvic region. In particular, neuromodulation ofthese nerve structures comprises inhibiting, reducing, blocking, pacing,up-regulating, and/or down-regulating neural communication along neuralfibers (e.g., efferent and/or afferent neural fibers) innervating themale reproductive organs (e.g., the testes, penis) or, in otherembodiments, innervating the female reproductive organs (e.g., thevulva, vagina, clitoris, uterus, and ovaries) for the treatment of pain.These targets can be intravenously accessed through femoral, brachial orradial approaches where a catheter could be navigated through thefemoral and iliac vessels (and its branches), and in some approachesthrough the aorta to the subsidiary arteries (e.g., testicular vessels,etc.). Such incapacitation, disruption, and/or regulation can belong-term (e.g., permanent or for periods of months, years, or decades)or short-term (e.g., for periods of minutes, hours, days, or weeks).While long-term disruption of sympathetic nerve fibers innervating thereproductive organs can be desirable for alleviating chronic orincalculable pain over longer periods of time, short-term modulation ofone or more of these nerve structures may also be desirable. Forexample, some patients suffering from vaginismus may benefit fromshort-term modulation to provide alleviation of pain and/or musclespasms of the vagina to address issues relating psychological fearsassociated with vaginal penetration.

Sympathetic neural activity via the nerve fibers innervating thereproductive organs, and particularly sympathetic afferent nerves, areresponsible for carrying pain signals from the reproductive visceraand/or other structures in the pelvic region to the brain in patientse.g., patients with conditions and diseases of the reproductive organsand genitalia, including, but not limited to, orchialgia, injury,Peyronie's disease, vulvodynia, dyspareunia, and vaginismus.Neuromodulation of the appropriate nerve structures are expected to beuseful in reducing perceived pain associated with these conditions, aswell as pain associated with plexopathy in the pelvic region. Methodsand systems for neuromodulation of these nerve structures forefficaciously treating and/or reducing pain associated with severalclinical conditions of the reproductive viscera and genitalia, aredescribed herein.

III. SELECTED EXAMPLES OF NEUROMODULATION MODALITIES

Various techniques can be used to partially or completely incapacitateneural pathways, such as those innervating the pancreas, the liver, thegallbladder or other abdominal organs. Such various techniques can alsobe used to partially or completely incapacitate neural pathways such asthose innervating the testes, penis, vulva, vagina, clitoris or otherreproductive organs. Neuromodulation in accordance with embodiments ofthe present technology can be electrically-induced, thermally-induced,chemically-induced, or induced in another suitable manner or combinationof manners at one or more suitable treatment locations during atreatment procedure. For example, the purposeful application ofradiofrequency (RF) energy (monopolar and/or bipolar), pulsed RF energy,microwave energy, optical energy, ultrasound energy (e.g.,intravascularly delivered ultrasound, extracorporeal ultrasound,high-intensity focused ultrasound (HIFU)), cryotherapeutic energy,direct heat energy, chemicals (e.g., drugs or other agents), radiation(e.g., infrared, visible, gamma), or combinations thereof to tissue at atreatment location can induce one or more desired effects at thetreatment location, e.g., broadly across the treatment location or atlocalized regions of the treatment location.

FIGS. 2A and 2B are anatomical views illustrating the abdominal viscera10 and the major arterial vessels including, for example, the aorta 12,the celiac artery 14 and the superior mesenteric artery 16. FIGS. 2A and2B also illustrate the sympathetic nerve structures that innervate theabdominal viscera 10, including the celiac plexus and/or celiac ganglion18, and the superior mesenteric plexus and/or ganglion 20. Treatmentprocedures for neuromodulation in accordance with embodiments of thepresent technology can include applying a treatment modality at one ormore treatment locations proximate a structure having a relatively highconcentration of sympathetic nerves innervating a diseased or otherwiseabnormal or targeted organ. In some embodiments, for example, at leastone treatment location can be proximate a portion of the celiac artery14, a branch of the celiac artery 14, an ostium of the celiac artery 15,and/or another suitable structure (e.g., another suitable structure inclose association the celiac plexus and/or celiac ganglion 18) in thevicinity of celiac sympathetic nerves. In other embodiments, at leastone treatment location can be proximate a portion of the superiormesenteric artery 16, a branch of the superior mesenteric artery 16, anostium of the superior mesenteric artery 17, a superior mesenteric vein(not shown), and/or another suitable structure (e.g., another suitablestructure in close association the superior mesenteric ganglion 18) inthe vicinity of superior mesenteric sympathetic nerves.

FIG. 2C, for example, is a cross-sectional view illustratingneuromodulation at a treatment location within the superior mesentericartery 16. As shown in FIG. 2C, a treatment device 22 including a shaft24 and a therapeutic element 26 can be extended toward the superiormesenteric artery 16 to locate the therapeutic element 26 at thetreatment location within the superior mesenteric artery 16. Thetherapeutic element 26 can be configured for neuromodulation at thetreatment location via a suitable treatment modality, e.g.,cryotherapeutic, direct heat, electrode-based, transducer-based,chemical-based, or another suitable treatment modality. Likewise, thetreatment device 22 can be located at a treatment location within theceliac artery 14 for administering neuromodulation. In otherembodiments, administering neuromodulation can include administering asuitable treatment modality at more than one site, e.g., the celiacartery 14 and the superior mesenteric artery 16, for example formodulating the sympathetic nerves innervating the pancreas or anotherabdominal organ.

FIG. 3A is a cross-sectional anatomical view illustrating a testicle 30,a testicular artery 32, and nearby structures and vessels. Treatmentprocedures for testicular neuromodulation for the treatment of pain, forexample, can include applying a treatment modality at one or moretreatment locations proximate a structure having a relatively highconcentration of sympathetic nerves innervating the testes. In someembodiments, for example, at least one treatment location can beproximate a portion of the testicular artery 32, a branch of thetesticular artery 32, an ostium of the testicular artery 32, atesticular vein, a branch of a testicular vein, an ostium of atesticular vein, and/or another suitable structure in the vicinity oftesticular nerves (e.g., nerves originating at the spermatic plexus, thegenital branch of the genitofemoral nerve). FIG. 3B, for example, is across-sectional view illustrating neuromodulation at a treatmentlocation within the testicular artery 32. As shown in FIG. 3B, atreatment device 34 including a shaft 36 and a therapeutic element 38can be extended toward the testicular artery 32 to locate thetherapeutic element 38 at the treatment location within the testicularartery 32. The therapeutic element 38 can be configured forneuromodulation at the treatment location via a suitable treatmentmodality, e.g., cryotherapeutic, direct heat, electrode-based,transducer-based, chemical-based, or another suitable treatmentmodality. The treatment device 34 may have a number of featuresgenerally similar to the treatment device 22 described above withreference to FIG. 2C. Further examples of suitable treatment devices aredescribed below with reference to FIG. 7.

FIG. 4 is a cross-sectional anatomical view illustrating a common iliacartery 40, an internal iliac artery 42, an external iliac artery 44, aninternal pudendal artery 46, a superior gluteal artery 48 and othernearby structures and vessels. Treatment procedures for neuromodulationof the male (testes, penis) or female (e.g., vulva, vagina, clitoris)reproductive organs for the treatment of pain can include, for example,applying a treatment modality at one or more treatment locationsproximate a structure having a relatively high concentration ofsympathetic nerves innervating these reproductive or genital structures.In some embodiments, for example, at least one treatment location can beproximate a portion/branch/ostium of the internal iliac artery 42 (orvein) for neuromodulation of a sacral plexus, a portion/branch/ostium ofthe external iliac artery 44 (or vein) for neuromodulation of a genitalbranch of a genitofemoral nerve, a portion/branch/ostium of the internalpudendal artery 46 (or vein) for neuromodulation of a pudendal nerve orperineal nerve, a portion/branch/ostium of the superior gluteal artery48 (or vein) for neuromodulation of a lumbosacral plexus, aportion/branch/ostium of the deep circumflex iliac artery (or vein)which is a branch of the external iliac artery 44 for neuromodulation ofa ilioinguinal nerve, and/or another suitable structure in the vicinityof nerves innervating the male or female reproductive organs.

FIG. 5 is an anatomical view illustrating a portion of the uterus 50,vagina 51, an ovary 52 and nearby organs and vessels, including avaginal artery 54 and a uterine artery 56. Treatment procedures forvaginal or uterine neuromodulation in accordance with embodiments of thepresent technology can include applying a treatment modality at one ormore treatment locations proximate a structure having a relatively highconcentration of vaginal or uterine nerves, respectively. In someembodiments, for example, at least one treatment location can beproximate a portion/branch/ostium of the vaginal artery 54 (or vein) forneuromodulation of a vaginal plexus or other vaginal nerve, aportion/branch/ostium of the uterine artery 56 (or vein) forneuromodulation of a uterine plexus or other uterine nerve, and/oranother suitable structure in the vicinity of sympathetic nervesinnervating the uterus and/or vagina.

The treatment location can be proximate (e.g., at or near) a vessel orchamber wall (e.g., a wall of a “target vessel” such as a celiac artery,superior mesenteric artery or vein, a testicular artery or vein, acommon iliac artery or vein, an internal iliac artery or vein, anexternal iliac artery or vein, an internal pudendal artery or vein, asuperior gluteal artery or vein, deep circumflex iliac artery or vein, avaginal artery or vein, a uterine artery or vein and/or another suitablestructure for the management or treatment of pain associated with theabdominal or reproductive viscera), and the treated tissue can includetissue proximate the treatment location. For example, with regard to aceliac artery, a treatment procedure can include modulating nerves inthe celiac plexus, which lay at least partially within or adjacent tothe adventitia of the celiac artery. In some embodiments it may bedesirable to modulate celiac nerves from a treatment location within avessel and in close proximity to a diseased or damaged abdominal organ(e.g., pancreas), for example, closer to the diseased or damaged organthan to a trunk of the vessel. This can increase the likelihood ofmodulating nerves specific to the organ or viscera, while decreasing thelikelihood of modulating nerves that extend to other organs. Vessels candecrease in diameter and become more tortuous as they extend toward anorgan (e.g., a diseased, damaged or otherwise target organ).Accordingly, modulating nerves from a treatment location in closeproximity to the target organ can include using a device (e.g.,treatment devices 22, 34) having size, flexibility, and/or othercharacteristics suitable for accessing narrow and/or tortuous portionsof vessels.

In some embodiments, the purposeful application of energy (e.g.,electrical energy, thermal energy, etc.) to tissue can induce one ormore desired thermal heating and/or cooling effects on localized regionsof the target vessels, for example, and adjacent regions along all or aportion of the targeted sympathetic nerve fibers, which lay intimatelywithin or adjacent to the adventitia of the target vessels. Someembodiments of the present technology, for example, includecryotherapeutic neuromodulation, which can include cooling tissue at atarget site in a manner that modulates neural function. The mechanismsof cryotherapeutic tissue damage include, for example, direct cellinjury (e.g., necrosis), vascular injury (e.g., starving the cell fromnutrients by damaging supplying blood vessels), and sublethalhypothermia with subsequent apoptosis. Exposure to cryotherapeuticcooling can cause acute cell death (e.g., immediately after exposure)and/or delayed cell death (e.g., during tissue thawing and subsequenthyperperfusion). Several embodiments of the present technology includecooling a structure at or near an inner surface of a vessel or chamberwall such that proximate (e.g., adjacent) tissue is effectively cooledto a depth where sympathetic (efferent and/or afferent) nerves reside.For example, a cooling structure can be cooled to the extent that itcauses therapeutically-effective, cryogenic nerve modulation.Sufficiently cooling at least a portion of a sympathetic nerve may slowor potentially block conduction of neural pain signals from a damaged ordiseased organ to the brain and/or to produce a prolonged or permanentreduction in organ sympathetic activity. In some embodiments, acryotherapeutic treatment modality can include cooling that is notconfigured to cause neuromodulation. For example, the cooling can be ator above cryogenic temperatures and can be used to controlneuromodulation via another treatment modality, e.g., to reduce damageto non-targeted tissue when targeted tissue adjacent to the non-targetedtissue is heated.

Cryotherapeutic treatment can be beneficial in certain embodiments. Forexample, rapidly cooling tissue can provide an analgesic effect suchthat cryotherapeutic treatment can be less painful than other treatmentmodalities. Neuromodulation using cryotherapeutic treatment cantherefore require less analgesic medication to maintain patient comfortduring a treatment procedure compared to neuromodulation using othertreatment modalities. Additionally, reducing pain can reduce patientmovement and thereby increase operator success and/or reduce proceduralcomplications. Cryogenic cooling also typically does not causesignificant collagen tightening, and therefore is not typicallyassociated with vessel stenosis. In some embodiments, cryotherapeutictreatment can include cooling at temperatures that can cause therapeuticelements to adhere to moist tissue. This can be beneficial because itcan promote stable, consistent, and continued contact during treatment.The typical conditions of treatment can make this an attractive featurebecause, for example, patients can move during treatment, cathetersassociated with therapeutic elements can move, and/or respiration cancause the internal organ structures to rise and fall and thereby movethe associated vasculature. In addition, blood flow is pulsatile and cancause structures associated with the target organs to pulse. Cryogenicadhesion also can facilitate intravascular positioning, particularly inrelatively small structures (e.g., relatively short arteries) in whichstable intravascular positioning can be difficult to achieve.

As an alternative to or in conjunction with cryotherapeutic cooling,other suitable energy delivery techniques, such as electrode-based ortransducer-based approaches, can be used for therapeutically-effectiveneuromodulation. Electrode-based or transducer-based treatment caninclude delivering electrical energy and/or another form of energy totissue and/or heating tissue at a treatment location in a manner thatmodulates neural function. For example, sufficiently stimulating and/orheating at least a portion of a sympathetic nerve can slow orpotentially block conduction of neural pain signals from a damaged ordiseased organ to the brain and/or to produce a prolonged or permanentreduction in sympathetic activity. As noted previously, suitable energymodalities can include, for example, RF energy (monopolar and/orbipolar), pulsed RF energy, microwave energy, ultrasound energy (e.g.,intravascularly delivered ultrasound, extracorporeal ultrasound, HIFU),extracorporeal ultrasound energy, laser energy, optical energy,magnetic, direct heat, or other suitable energy modalities alone or incombination. Where a system uses a monopolar configuration, a returnelectrode or ground patch fixed externally on the subject can be used.Moreover, electrodes (or other energy delivery elements) can be usedalone or with other electrodes in a multi-electrode array. Examples ofsuitable multi-electrode devices are described in U.S. patentapplication Ser. No. 13/281,360, filed Oct. 25, 2011, and incorporatedherein by reference in its entirety. Other suitable devices andtechnologies, such as cryotherapeutic devices, are described in U.S.patent application Ser. No. 13/279,330, filed Oct. 23, 2011, andadditional thermal devices are described in U.S. patent application Ser.No. 13/279,205, filed Oct. 21, 2011, each of which are incorporatedherein by reference in their entireties.

Thermal effects can include both thermal ablation and non-ablativethermal alteration or damage (e.g., via sustained heating and/orresistive heating) to partially or completely disrupt the ability of anerve to transmit a signal. Desired thermal heating effects, forexample, may include raising the temperature of target neural fibersabove a desired threshold to achieve non-ablative thermal alteration, orabove a higher temperature to achieve ablative thermal alteration. Forexample, the target temperature can be above body temperature (e.g.,approximately 37° C.) but less than about 45° C. for non-ablativethermal alteration, or the target temperature can be about 45° C. orhigher for ablative thermal alteration. More specifically, exposure tothermal energy in excess of a body temperature of about 37° C., butbelow a temperature of about 45° C., may induce thermal alteration viamoderate heating of target neural fibers or of vascular structures thatperfuse the target fibers. In cases where vascular structures areaffected, the target neural fibers may be denied perfusion resulting innecrosis of the neural tissue. For example, this may induce non-ablativethermal alteration in the fibers or structures. Exposure to heat above atemperature of about 45° C., or above about 60° C., may induce thermalalteration via substantial heating of the fibers or structures. Forexample, such higher temperatures may thermally ablate the target neuralfibers or the vascular structures that perfuse the target fibers. Insome patients, it may be desirable to achieve temperatures thatthermally ablate the target neural fibers or the vascular structures,but that are less than about 90° C., or less than about 85° C., or lessthan about 80° C., and/or less than about 75° C. Other embodiments caninclude heating tissue to a variety of other suitable temperatures.

In some embodiments, neuromodulation can include a chemical-basedtreatment modality alone or in combination with another treatmentmodality. Neuromodulation using chemical-based treatment can includedelivering one or more chemicals (e.g., drugs or other agents) to tissueat a treatment location in a manner that modulates neural function. Thechemical, for example, can be selected to affect the treatment locationgenerally or to selectively affect some structures at the treatmentlocation over other structures. For example, the chemical can beguanethidine, ethanol, phenol, vincristine, a neurotoxin, or anothersuitable agent selected to alter, damage, or disrupt nerves. In someembodiments, energy (e.g., light, ultrasound, or another suitable typeof energy) can be used to activate the chemical and/or to cause thechemical to become more bioavailable. A variety of suitable techniquescan be used to deliver chemicals to tissue at a treatment location. Forexample, chemicals can be delivered via one or more devices, such asneedles originating outside the body or within the vasculature ordelivery pumps (see, e.g., U.S. Pat. No. 6,978,174, the disclosure ofwhich is hereby incorporated by reference in its entirety). In anintravascular example, a catheter can be used to intravascularlyposition a therapeutic element including a plurality of needles (e.g.,micro-needles) that can be retracted or otherwise blocked prior todeployment. In other embodiments, a chemical can be introduced intotissue at a treatment location via simple diffusion through a vesselwall, electrophoresis, or another suitable mechanism. Similar techniquescan be used to introduce chemicals that are not configured to causeneuromodulation, but rather to facilitate neuromodulation via anothertreatment modality. Examples of such chemicals include, but are notlimited to, anesthetic agents and contrast agents.

In some embodiments, a treatment procedure can include applying asuitable treatment modality at a treatment location in a testing stepfollowed by a treatment step. The testing step, for example, can includeapplying the treatment modality at a lower intensity and/or for ashorter duration than during the treatment step. This can allow anoperator to determine (e.g., by neural activity sensors and/or patientfeedback) whether nerves proximate the treatment location are suitablefor modulation. Performing a testing step can be particularly useful fortreatment procedures in which targeted nerves are closely associatedwith nerves that could cause undesirable side effects if modulatedduring a subsequent treatment step.

IV. ACHIEVING INTRAVASCULAR ACCESS TO THE TARGET VESSELS

In accordance with the present technology, neuromodulation of a leftand/or right celiac plexus and/or celiac ganglion 18 (FIG. 2A), which isintimately associated with a celiac artery 14 (FIG. 2A), may be achievedthrough intravascular access. Further, neuromodulation of a superiormesenteric ganglion 20 (FIG. 2A), which is intimately associated with asuperior mesenteric artery 16 (FIG. 2A), may also be achieved throughintravascular access. As FIG. 6A shows, blood moved by contractions ofthe heart is conveyed from the left ventricle of the heart by the aorta.The aorta descends through the thorax and bifurcates at the left andright iliac arteries. The left and right iliac arteries descend,respectively, through the left and right legs and join the left andright femoral arteries.

As FIG. 6B shows, the blood collects in veins and returns to the heart,through the femoral veins into the iliac veins and into the inferiorvena cava. Above the renal veins, the inferior vena cava ascends toconvey blood into the right atrium of the heart. From the right atrium,the blood is pumped through the right ventricle into the lungs, where itis oxygenated. From the lungs, the oxygenated blood is conveyed into theleft atrium. From the left atrium, the oxygenated blood is conveyed bythe left ventricle back to the aorta.

As will be described in greater detail later, the femoral artery may beaccessed and cannulated at the base of the femoral triangle justinferior to the midpoint of the inguinal ligament. A catheter (notshown) may be inserted percutaneously into the femoral artery throughthis access site, passed through the iliac artery and aorta, and placedinto either the celiac artery 14 or the superior mesenteric artery 16(FIG. 2A) for the management and/or treatment of pain associated withthe abdominal viscera 10 (FIGS. 2A-2B). This route comprises anintravascular path that offers minimally invasive access to a respectiveceliac artery 14, superior mesenteric artery 16 and/or other bloodvessels (e.g., superior mesenteric vein, not shown). Alternatively, thewrist, upper arm, and shoulder region provide other locations forintroduction of catheters into the arterial system. For example,catheterization of either the radial, brachial, or axillary artery maybe utilized in select cases. Catheters introduced via these accesspoints may be passed through the subclavian artery on the left side (orvia the subclavian and brachiocephalic arteries on the right side),through the aortic arch, down the descending aorta and into the celiacand/or superior mesenteric arteries using standard angiographictechnique.

In accordance with another embodiment of the present technology,neuromodulation of a left and/or right spermatic plexus, which isintimately associated with a left and/or right testicular artery 32(FIG. 3A), may be achieved through intravascular access. Referring backto FIGS. 6A and 6B, a catheter may be inserted percutaneously into thefemoral artery through this access site, passed through the iliac arteryand aorta, and placed into either the left or right testicular artery 32(FIG. 3A) for the management and/or treatment of pain associated withthe testes 30 (FIGS. 3A and 3B). For the management and/or treatment ofpain associated with the testes and penis in males or the vulva andclitoris in females, neuromodulation of a genital branch ofgenitofemoral nerve, which is intimately associated with an externaliliac artery 44 (FIG. 4), may also be achieved through intravascularaccess by percutaneously inserting a catheter into either the left orright femoral artery (FIG. 6A), into the respective left or right commoniliac artery 40 (FIGS. 4 and 6A) and down into the external iliac artery44 (FIG. 4). Further, neuromodulation of the ilioinguinal nerve may alsobe achieved by accessing the deep circumflex iliac artery off of theexternal iliac artery 44 (FIG. 4). Additional targets for themanagement/treatment of pain associated with male and femalegenitalia/reproductive organs include the sacral plexus, which isintimately associated with a left and/or right internal iliac artery 42(FIG. 4) or vein, and the pudendal and perineal nerves, both of whichare intimately associated with left and/or right internal pudendalarteries 46 (FIG. 4) and veins. Percutaneous intravascular access tothese nerve structures can include passing a catheter through the leftor right femoral artery (FIG. 6A), into the respective left or rightcommon iliac artery 40 (FIGS. 4 and 6A) and down into the internal iliacartery 44 (FIG. 4) and into the internal pudendal artery 46 (FIG. 4), ifdesired.

In accordance with a further embodiment of the present technology,neuromodulation of a left or right vaginal plexus, which is intimatelyassociated with a left or right vaginal artery 54 (FIG. 5), andneuromodulation of a left or right uterine plexus, which is intimatelyassociated with a left or right uterine artery 56 (FIG. 5) may beachieved through intravascular access. Referring to FIGS. 5, 6A, and 6Btogether, a catheter (not shown) may be inserted percutaneously into theleft or right femoral artery through this access site, passed throughthe left or right iliac artery and the internal iliac artery,respectively, and placed into either the left or right vaginal artery 54or uterine artery 56 (FIG. 5) for the management and/or treatment ofpain associated with the vagina 51 or uterus 50, respectively (FIG. 5).

V. PROPERTIES AND CHARACTERISTICS OF THE ABDOMINAL AND REPRODUCTIVEORGAN VASCULATURE

Properties and characteristics of the abdominal and reproductive organvasculature impose challenges to both access and treatment methods, andto system/device designs. Since neuromodulation of the varioussympathetic nerve structures innervating the abdominal viscera (e.g.,celiac plexus, superior mesenteric plexus) or the reproductive viscera(e.g., spermatic plexus, vaginal plexus, uterine plexus, genitofemoralnerve, ilioinguinal nerve, pudendal nerve perineal nerve, etc.) may beachieved in accordance with embodiments of the present technologythrough intravascular access, various aspects of the design ofapparatus, systems, and methods for achieving such neuromodulation aredisclosed herein. Aspects of the technology disclosed herein addressadditional challenges associated with variation of physiologicalconditions and architecture across the patient population and/or withina specific patient across time, as well as in response to diseasestates, such as pancreatitis or pancreatic cancer. For example, thedesign of the intravascular device and treatment protocols can addressnot only material/mechanical, spatial, fluid dynamic/hemodynamic and/orthermodynamic properties, but also provide particular algorithms andfeedback protocols for delivering energy and obtaining real-timeconfirmatory results of successfully delivering energy to an intendedtarget location in a patient-specific manner.

As discussed previously, a catheter may be advanced percutaneously intoeither the desired vasculature targets via a minimally invasiveintravascular path. However, minimally invasive arterial or venousaccess may be challenging, for example, because as compared to someother larger arteries that are routinely accessed using catheters, someof the target arteries (e.g., testicular arteries, internal iliacartery, etc.) can be tortuous, may be of relatively small diameter,and/or may require adjustments to the length and flexibility of thecatheters. Arterial anatomy also may vary significantly from patient topatient, which further complicates minimally invasive access.Significant inter-patient variation may be seen, for example, inrelative tortuosity, diameter, and/or length. Apparatus, systems andmethods for achieving neuromodulation via intravascular access canaccount for these and other aspects of arterial anatomy and itsvariation across the patient population when minimally invasivelyaccessing an artery. For example, spiral or helical computed tomography(CT) technology can be used to produce 3D images of the vascularfeatures for individual patients, and intravascular path choice as wellas device size/diameter, length, flexibility, torque-ability, kinkresistance, etc. can be selected based upon the patient's specificvascular features.

In addition to complicating arterial access, specifics of the abdominalor reproductive anatomy also complicate establishment of stable contactbetween neuromodulatory apparatus and a luminal surface or wall of anartery or vein. When the neuromodulatory apparatus includes an energydelivery element, such as an electrode, transducer, heating element or acryotherapeutic device, consistent positioning and appropriate contactforce applied by the energy or cryotherapy delivery element to thevessel wall, and adhesion between the applicator and the vessel wall canbe important for predictability. However, navigation can be impeded bythe tight space within an artery, as well as tortuosity of the artery.Furthermore, establishing consistent contact can be complicated bypatient movement, respiration, and/or the cardiac cycle because thesefactors may cause significant movement of the artery relative to theaorta, for example, and the cardiac cycle may transiently distend thetarget artery (i.e., cause the wall of the artery to pulse). To addressthese challenges, the treatment device or applicator may be designedwith relative sizing and flexibility considerations. For example, theartery may have an internal diameter less than approximately 1.7 mm andthe treatment device can be delivered using a 3 French, or in somecases, a 4 French sized catheter. To address challenges associated withpatient and/or arterial movement during treatment, the treatment deviceand neuromodulation system can be configured to use sensory feedback,such as impedance and temperature, to detect instability and to alertthe operator to reposition the device and/or to temporarily stoptreatment. In other embodiments, energy delivery algorithms can bevaried in real-time to account for changes detected due to patientand/or arterial movement. In further examples, the treatment device mayinclude one or more modifications or movement resistant enhancementssuch as atraumatic friction knobs or barbs on an outside surface of thedevice for resisting movement of the device relative to the desiredtissue location, positionable balloons for inflating and holding thedevice in a consistent and stable position during treatment, or thedevice can include a cryogenic component that can temporarily freeze oradhere the device to the desired tissue location.

After accessing a desired target artery and facilitating stable contactbetween neuromodulatory apparatus and a luminal surface of the artery,nerves in and around the adventitia of the artery can be modulated viathe neuromodulatory apparatus. Effectively applying thermal treatmentfrom within an artery is non-trivial given the potential clinicalcomplications associated with such treatment. For example, the intimaand media of the artery are highly vulnerable to thermal injury. Asdiscussed in greater detail below, the intima-media thickness separatingthe vessel lumen from its adventitia means that target nerves may bemultiple millimeters distant (e.g., 1-3 mm) from the luminal surface ofthe artery. Sufficient energy can be delivered to or heat removed fromthe target sympathetic nerve fibers to modulate the target nerveswithout excessively cooling or heating the vessel wall to the extentthat the wall is frozen, desiccated, or otherwise potentially affectedto an undesirable extent. For example, when employing energy modalitiessuch as RF or ultrasound, energy delivery can be focused on a locationfurther from the interior vessel wall. In one embodiment, the majorityof the RF or ultrasound energy can be focused on a location (e.g., a“hot spot”) 1-3 mm beyond the interior surface of the vessel wall. Theenergy will dissipate from the hot spot in a radially decreasing manner.Thus, the targeted nerves can be modulated without damage to the luminalsurface of the vessel. A potential clinical complication associated withexcessive heating is thrombus formation from coagulating blood flowingthrough the artery. Given that this thrombus may cause irreversibledamage to the abdominal or reproductive organ, thermal treatment fromwithin the artery can be applied carefully. Accordingly, the complexfluid mechanics and thermodynamic conditions present in the arteryduring treatment, particularly those that may impact heat transferdynamics at the treatment site, may be important in applying energy(e.g., heating thermal energy) and/or removing heat from the tissue(e.g., cooling thermal conditions) from within the artery.

The neuromodulatory apparatus can also be configured to allow foradjustable positioning and repositioning of a thermal energy deliveryelement (e.g., electrode, transducer, heating element, cryotherapeuticelement or device, etc.) within the artery since location of treatmentmay also impact clinical efficacy. For example, it may be tempting toapply a full circumferential treatment from within the artery given thatthe nerves may be spaced circumferentially around an artery. In somesituations, a full-circle lesion likely resulting from a continuouscircumferential treatment may be potentially related to artery stenosis.Therefore, the formation of more complex lesions along a longitudinaldimension of the artery via the cryotherapeutic devices or other energydelivery elements (e.g., electrodes, transducers, etc.) and/orrepositioning of the neuromodulatory apparatus to multiple treatmentlocations may be desirable. It should be noted, however, that a benefitof forming a circumferential lesion or ablation may outweigh thepotential of artery stenosis or the risk may be mitigated with certainembodiments or in certain patients and forming a circumferential lesionor ablation could be a goal. Additionally, variable positioning andrepositioning of the neuromodulatory apparatus may prove to be useful incircumstances where the artery is particularly tortuous or where thereare proximal branch vessels off the artery main vessel, making treatmentin certain locations challenging.

Blood flow through an artery may be temporarily occluded for a shorttime with minimal or no complications. However, occlusion for asignificant amount of time can be avoided in some cases to preventinjury to the organ such as ischemia. It can be beneficial to avoidocclusion altogether or, if occlusion is beneficial, to limit theduration of occlusion (e.g., 2-5 minutes).

VI. METHODS FOR TREATMENT AND MANAGEMENT OF PAIN

Disclosed herein are several embodiments of methods directed totreatment or management of pain associated with the abdominal and/orreproductive viscera using neuromodulation. The methods disclosed hereinmay represent various advantages over a number of conventionalapproaches and techniques in that they allow for the potential targetingof sympathetic nerve fibers (e.g., afferent nerve fibers) that transmitpain information from nociceptive receptors at a disease or damagedorgan site to the cortex of the brain, thereby alleviating or reducingthe sensation of pain. In some embodiments, the neuromodulation may alsoreduce an elevated sympathetic drive, which may contribute to multiplemanifestations of disease states. Also, the disclosed methods providefor localized treatment and limited duration treatment regimens (e.g.,one-time treatment), thereby reducing patient long-term treatmentcompliance issues, side-effects from long-term usage of painmedications, etc.

In certain embodiments, the methods provided herein comprise performingneuromodulation, thereby decreasing sympathetic nerve activity (e.g.,afferent nerve activity), reducing transmission of pain information froma diseased or damaged organ site and alleviating or reducing thesensation of pain experienced by the patient. Neuromodulation may berepeated one or more times at various intervals until a desiredsympathetic nerve activity level or another therapeutic benchmark isreached. In one embodiment, a decrease in sympathetic nerve activityand/or a reduction in transmission of pain signals from adiseased/damaged organ site can be evaluated by assessing a pain leveland/or level of function of in the patient following the neuromodulationtreatment procedure. For example, a patient can be assessed for painlevel, quality, and/or level of function using one or more painmeasurement scales such as the standardized Visual Analog Scale (VAS)shown in FIG. 1A both before a neuromodulation treatment and following aneuromodulation treatment. In another embodiment, for example, adecrease in sympathetic nerve activity may be observed via a marker ofsympathetic nerve activity in patients experiencing pain, such asdecreased levels of plasma norepinephrine (noradrenaline). Othermeasures or markers of sympathetic nerve activity can include musclesympathetic nerve activity (MSNA), norepinephrine spillover, and/orheart rate variability.

In certain embodiments of the methods provided herein, neuromodulationis expected to result in a change in sympathetic nerve activity over aspecific timeframe. For example, in certain of these embodiments,sympathetic nerve activity levels and/or a reported level of pain aredecreased over an extended timeframe, e.g., within 1 month, 2 months, 3months, 6 months, 9 months or 12 months post-neuromodulation. In aspecific embodiment, a reported level of pain (e.g., as assessed on oneor more pain measurement scales, FIGS. 1A-1E), can be decreased by about5%, about 10%, about 15%, about 20%, about 30%, about 40%, about 50%,about 75%, or about 90%. In other embodiments, patients may report thatno measurable pain is experienced following a neuromodulation procedure.

In several embodiments, the methods disclosed herein may comprise anadditional step of measuring sympathetic nerve activity levels, and incertain of these embodiments, the methods can further comprise comparingthe activity level to a baseline activity level. Such comparisons can beused to monitor therapeutic efficacy and to determine when and if torepeat the neuromodulation procedure. In certain embodiments, a baselinesympathetic nerve activity level is derived from the subject undergoingtreatment. For example, baseline sympathetic nerve activity level may bemeasured in the subject at one or more timepoints prior to treatment. Abaseline sympathetic nerve activity value may represent sympatheticnerve activity at a specific timepoint before neuromodulation, or it mayrepresent an average activity level at two or more timepoints prior toneuromodulation. In certain embodiments, the baseline value is based onsympathetic nerve activity immediately prior to treatment (e.g., afterthe subject has already been catheterized). Alternatively, a baselinevalue may be derived from a standard value for sympathetic nerveactivity observed across the population as a whole or across aparticular subpopulation. In certain embodiments, post-neuromodulationsympathetic nerve activity levels are measured in extended timeframespost-neuromodulation, e.g., 3 months, 6 months or 12 monthspost-neuromodulation.

In certain embodiments of the methods provided herein, the methods aredesigned to decrease sympathetic nerve activity to a target level. Inthese embodiments, the methods include a step of measuring sympatheticnerve activity levels post-neuromodulation (e.g., 6 monthspost-treatment, 12 months post-treatment, etc.) and comparing theresultant activity level to a baseline activity level as discussedabove. In certain of these embodiments, the treatment is repeated untilthe target sympathetic nerve activity level is reached. In otherembodiments, the methods are simply designed to decrease sympatheticnerve activity below a baseline level without requiring a particulartarget activity level.

Neuromodulation may be performed on a patient having chronicdebilitating or intractable pain or having one or more positivediagnosis of a condition or disease associated with chronic pain (e.g.,pancreatitis, pancreatic cancer, Orchialgia, vulvodynia, etc.) to reduceone or more measurable physiological pain levels corresponding to thechronic pain. In certain embodiments of the methods provided herein, themethods are designed to decrease or reduce a patient-perceived orclinician-observed level of pain (e.g., quality, quantity, level offunction, etc.) to a target level. In these embodiments, the methodsinclude a step of measuring pain levels using, for example, one or morepain scales (FIGS. 1A-1E) before neuromodulation. In some cases, thepre-neuromodulation level of pain can be an average level of pain (e.g.,averaged over days, weeks, months, years) reported by the patient orobserved by a qualified observant (e.g., clinician). The methods canalso include a step of measuring pain levels using at least one of thesame pain scales used pre-neuromodulation to assess levels of painpost-neuromodulation (e.g., 1 month post-treatment, 3 monthspost-treatment, 6 months post-treatment, 12 months post-treatment, etc.)and comparing the resultant pain level to the pre-neuromodulation painlevel as discussed above. In certain of these embodiments, the treatmentis repeated until the target pain level is reached. In otherembodiments, the methods are simply designed to decrease a pain levelbelow a desired baseline pain level without requiring a particulartarget pain level.

In a particular example, a patient having chronic pain associated with adisease or condition of an abdominal organ (e.g., pancreas, liver,gallbladder, etc.) can be assessed pre-neuromodulation for a level ofpain intensity using the VAS. The patient's mark on the VAS line can betranslated to a score from 1 to 10. The patient can undergoneuromodulation treatment targeting the celiac plexus (via the celiacartery), the superior mesenteric plexus (via the superior mesentericartery or vein), or both. The patient can be assessedpost-neuromodulation for a level of pain intensity using the VAS wherethe patient's mark on the VAS line can be translated to a score from 1to 10. In one embodiment, the post-neuromodulation score is less thanthe pre-neuromodulation score after a determined amount of time, e.g.,within 1 month, 2 months, 3 months, 6 months, 9 months or 12 monthspost-neuromodulation. In particular embodiments, thepost-neuromodulation score is less than the pre-neuromodulation score byan amount greater than about 20%, about 30%, about 50%, about 70%, orabout 90%. In addition to or instead of affecting the intensity of painas determined by a VAS score, for example, neuromodulation may increasea patient's function level (e.g., as assessed by a functional painscale, FIG. 1E).

In some embodiments, reduction of sympathetic activity of target nervesvia neuromodulation may also reduce elevated central sympathetic drive.In some embodiments, neuromodulation of a target sympathetic nerve canbe used to reduce central sympathetic drive in a patient diagnosed witha damaged or diseased organ that is associated with chronic pain. Insome embodiments, for example, MSNA can be reduced by at least about 10%in the patient within about three months after at least partiallyinhibiting sympathetic neural activity in nerves proximate a targetblood vessel innervating the damaged or diseased organ. Similarly, insome instances local norepinephrine spillover to plasma can be reducedat least about 20% in the patient within about three months after atleast partially inhibiting sympathetic neural activity in nervesproximate a target blood vessel innervating the organ. Additionally,measured local norepinephrine content (e.g., assessed via biopsy,assessed in real-time via intravascular blood collection techniques,etc.) can be reduced (e.g., at least about 5%, 10%, or in anotherembodiment, by at least 20%) in the patient within about three monthsafter at least partially inhibiting sympathetic neural activity innerves proximate a target blood vessel innervating the organ.

In another prophetic example, a male patient diagnosed with orchialgiacan be subjected to a baseline assessment (e.g., self-reporting)indicating a first set of measurable pain levels corresponding to theorchialgia. Such parameters can include, for example, perceived painintensity, pain quality, and level of function/activity. Followingbaseline assessment, the patient can be subjected to a testicularneuromodulation procedure. Such a procedure can, for example, includeany of the treatment modalities described herein or another treatmentmodality in accordance with the present technology. The treatment can beperformed on nerves proximate one or both testes of the patient.Following the treatment (e.g., 1, 3, 6, or 12 months following thetreatment), the patient can be subjected to a follow-up assessment. Thefollow-up assessment can indicate a measurable improvement in one ormore measurable pain levels corresponding to the orchialgia.

The methods described herein address the pain information transmittedfrom nociceptive receptors at a disease or damaged organ site to thecortex of the brain via sympathetic nerve fibers (e.g., afferent nervefibers). In contrast, known therapies currently prescribed for chronicpain sufferers typically address require long-term use of painmedications and other pharmaceutical agents which can have significantlimitations including limited efficacy, undesirable side effects and canbe subject to adverse or undesirable drug interactions when used incombination. In contrast, neuromodulation can be a one-time treatmentthat would be expected to have durable benefits to inhibit the long-termpain signal transmission and thereby achieve a favorable patientoutcome.

In some embodiments, patients experiencing and/or diagnosed with chronicpain can be treated with neuromodulation alone. However, in otherembodiments, patients diagnosed with diseases/conditions of theabdominal and/or reproductive viscera and experiencing chronic orintractable pain can be treated with combinations of therapics forreducing a level of perceived pain. For example, combinations oftherapies can be tailored based on specific manifestations of thedisease in a particular patient. In a specific example, patients havingchronic pain associated with pancreatic cancer can be treated withanti-cancer therapy (e.g., chemotherapy drugs, radiation, etc.) andceliac plexus and/or superior mesenteric plexus neuromodulation. Inanother example, neuromodulation can be combined with pain medications(e.g., analgesics) and/or other agents (e.g., anesthetics,antidepressants, antiepileptics, narcotics, etc.).

Treatment of chronic pain or related conditions may refer to eliminatingthe pain, slowing the onset or rate of development of the pain, reducingthe risk of developing pain typically associated with a diseased/damagedorgan, preventing or delaying the development of additional symptomsassociated with the chronic pain, reducing or ending symptoms associatedwith the chronic pain, generating a complete or partial regression ofthe pain, or some combination thereof.

VII. SELECTED EMBODIMENTS OF NEUROMODULATION SYSTEMS AND DEVICES

FIG. 7 is a partially schematic diagram illustrating a neuromodulationsystem 100 (“system 100”) configured in accordance with an embodiment ofthe present technology. The system 100 can include a treatment device102, an energy source or console 104 (e.g., a RF energy generator, acryotherapy console, etc.), and a cable 106 extending between thetreatment device 102 and the console 104. The treatment device 102 caninclude a handle 108, a neuromodulation assembly 110, and an elongatedshaft 112 extending between the handle 108 and the neuromodulationassembly 110. The shaft 112 can be configured to locate theneuromodulation assembly 110 intravascularly at a treatment location(e.g., in or near a celiac artery, superior mesenteric artery or vein, atesticular artery or vein, a common iliac artery or vein, an internaliliac artery or vein, an external iliac artery or vein, an internalpudendal artery or vein, a superior gluteal artery or vein, deepcircumflex iliac artery or vein, a vaginal artery or vein, a uterineartery or vein and/or another suitable structure for the management ortreatment of pain associated with the abdominal or reproductiveviscera), and the neuromodulation assembly 110 can be configured toprovide or support therapeutically-effective neuromodulation at thetreatment location. In some embodiments, the shaft 112 and theneuromodulation assembly 110 can be 3, 4, 5, 6, or 7 French or anothersuitable size. Furthermore, the shaft 112 and the neuromodulationassembly 110 can be partially or fully radiopaque and/or can includeradiopaque markers corresponding to measurements, e.g., every 5 cm.

Intravascular delivery can include percutaneously inserting a guide wire(not shown) within the vasculature and moving the shaft 112 and theneuromodulation assembly 110 along the guide wire until theneuromodulation assembly 110 reaches the treatment location. Forexample, the shaft 12 and the neuromodulation assembly 110 can include aguide-wire lumen (not shown) configured to receive the guide wire in anover-the-wire (OTW) or rapid-exchange (RX) configuration. Other bodylumens (e.g., ducts or internal chambers) can be treated, for example,by non-percutaneously passing the shaft 12 and neuromodulation assembly110 through externally accessible passages of the body or other suitablemethods. In some embodiments, a distal end of the neuromodulationassembly 110 can terminate in an atraumatic rounded tip or cap (notshown). The treatment device 102 can also be a steerable ornon-steerable catheter device (e.g., a guide catheter) configured foruse without a guide wire.

The neuromodulation assembly 110 can have a single state orconfiguration, or it can be convertible between a plurality of states orconfigurations. For example, the neuromodulation assembly 110 can beconfigured to be delivered to the treatment location in a delivery stateand to provide or support therapeutically-effective neuromodulation in adeployed state. In these and other embodiments, the neuromodulationassembly 110 can have different sizes and/or shapes in the delivery anddeployed states. For example, the neuromodulation assembly 110 can havea low-profile configuration in the delivery state and an expandedconfiguration in the deployed state. In another example, theneuromodulation assembly 110 can be configured to deflect into contactwith a vessel wall in a delivery state. The neuromodulation assembly 110can be converted (e.g., placed or transformed) between the delivery anddeployed states via remote actuation, e.g., using an actuator 114 of thehandle 108. The actuator 114 can include a knob, a pin, a lever, abutton, a dial, or another suitable control component. In otherembodiments, the neuromodulation assembly 110 can be transformed betweenthe delivery and deployed states using other suitable mechanisms ortechniques.

In some embodiments, the neuromodulation assembly 110 can include anelongated member (not shown) that can be configured to curve (e.g.,arch) in the deployed state, e.g., in response to movement of theactuator 114. For example, the elongated member can be at leastpartially helical/spiral in the deployed state. In other embodiments,the neuromodulation assembly 110 can include a balloon (not shown) thatcan be configured to be at least partially inflated in the deployedstate. An elongated member, for example, can be well suited for carryingone or more heating elements, electrodes or transducers and fordelivering heat, electrode-based or transducer-based treatment. Aballoon, for example, can be well suited for containing refrigerant(e.g., during or shortly after liquid-to-gas phase change) and fordelivering cryotherapeutic treatment. A balloon can also be used in someembodiments for carrying suitable RF conducting electrodes. In someembodiments, the neuromodulation assembly 110 can be configured forintravascular and/or transvascular delivery of chemicals. For example,the neuromodulation assembly 110 can include one or more openings (notshown), and chemicals (e.g., drugs or other agents) can be deliverablethrough the openings. For transvascular delivery, the neuromodulationassembly 110 can include one or more needles (not shown) (e.g.,retractable needles) and the openings can be at end portions of theneedles.

The console 104 is configured to control, monitor, supply, or otherwisesupport operation of the treatment device 102. In some embodiments, theconsole 104 can be separate from and in communication with the treatmentdevice 102. In other embodiments, the console 104 can be containedwithin or be a component of the treatment device 102. In still furtherembodiments, the treatment device 102 can be self-contained and/orotherwise configured for operation without connection to the console104. As shown in FIG. 7, the console 104 can include a primary housing116 having a display 118. The system 100 can include a control device120 along the cable 106 configured to initiate, terminate, and/or adjustoperation of the treatment device 102 directly and/or via the console104. In other embodiments, the system 100 can include another suitablecontrol mechanism. For example, the control device 120 can beincorporated into the handle 108. The console 104 can be configured toexecute an automated control algorithm 122 and/or to receive controlinstructions from an operator. Furthermore, console 104 can beconfigured to provide feedback to an operator before, during, and/orafter a treatment procedure via the display 118 and/or anevaluation/feedback algorithm 124. In some embodiments, the console 104can include a processing device (not shown) having processing circuitry,e.g., a microprocessor. The processing device can be configured toexecute stored instructions relating to the control algorithm 122 and/orthe evaluation/feedback algorithm 124. Furthermore, the console 104 canbe configured to communicate with the treatment device 102, e.g., viathe cable 106. For example, the neuromodulation assembly 110 of thetreatment device 102 can include a sensor (not shown) (e.g., a recordingelectrode, a temperature sensor, a pressure sensor, or a flow ratesensor) and a sensor lead (not shown) (e.g., an electrical lead or apressure lead) configured to carry a signal from the sensor to thehandle 108. The cable 106 can be configured to carry the signal from thehandle 108 to the console 104.

The console 104 can have different configurations depending on thetreatment modality of the treatment device 102. For example, when thetreatment device 102 is configured for electrode-based ortransducer-based treatment, the console 104 can include an energygenerator (not shown) configured to generate RF energy, pulsed RFenergy, microwave energy, optical energy, ultrasound energy (e.g.,intravascularly delivered ultrasound, extracorporeal ultrasound, HIFU),direct heat energy, magnetic energy, radiation (e.g., infrared, visible,gamma), or another suitable type of energy. In some embodiments, forexample, the console 104 can include a RF generator operably coupled toone or more electrodes (not shown) of the neuromodulation assembly 110.

When the treatment device 102 is configured for cryotherapeutictreatment, the console 104 can include a refrigerant reservoir (notshown) and can be configured to supply the treatment device 102 withrefrigerant, e.g., pressurized refrigerant in liquid or substantiallyliquid phase. Similarly, when the treatment device 102 is configured forchemical-based treatment, the console 104 can include a chemicalreservoir (not shown) and can be configured to supply the treatmentdevice 102 with one or more chemicals. In some embodiments, thetreatment device 102 can include an adapter (not shown) (e.g., a luerlock) configured to be operably coupled to a syringe (not shown). Theadapter can be fluidly connected to a lumen (not shown) of the treatmentdevice 102, and the syringe can be used, for example, to manuallydeliver one or more chemicals to the treatment location, to withdrawmaterial from the treatment location, to inflate a balloon (not shown)of the neuromodulation assembly 110, to deflate a balloon of theneuromodulation assembly 110, or for another suitable purpose. In otherembodiments, the console 104 can have other suitable configurations.

In certain embodiments, a neuromodulation device for use in the methodsdisclosed herein may combine two or more energy modalities. For example,the device may include both a hyperthermic source of ablative ormodulating energy and a hypothermic source, making it capable of, forexample, performing both RF neuromodulation and cryo-neuromodulation.The distal end of the treatment device may be straight (for example, afocal catheter), expandable (for example, an expanding mesh orcryoballoon), or have any other configuration (e.g., a helical coil).Additionally or alternatively, the treatment device may be configured tocarry out one or more non-ablative neuromodulatory techniques. Forexample, the device may comprise a means for diffusing a drug orpharmaceutical compound at the target treatment area (e.g., a distalspray nozzle).

VIII. SELECTED EXAMPLES OF TREATMENT PROCEDURES FOR NEUROMODULATION

Referring back to FIGS. 2A-5, in some embodiments the shaft(s) 24 or 36and the therapeutic element(s) 26 or 38 can be portions of a treatmentdevice at least partially corresponding to the treatment device 102shown in FIG. 7. The therapeutic element(s) 26 or 38, for example, canbe configured to radially expand into a deployed state at the treatmentlocation. In the deployed state, the therapeutic element(s) 26 or 38 canbe configured to contact an inner wall of a vessel of the targetvasculature and to form a suitable lesion or pattern of lesions withoutthe need for repositioning. For example, the therapeutic element(s) 26or 38 can be configured to form a single lesion or a series of lesions,e.g., overlapping or non-overlapping. In some embodiments, the lesion orpattern of lesions can extend around generally the entire circumferenceof the vessel, but can still be non-circumferential at longitudinalsegments or zones along a lengthwise portion of the vessel. This canfacilitate precise and efficient treatment with a low possibility ofvessel stenosis. In other embodiments, the therapeutic element(s) 26 or38 can be configured form a partially-circumferential lesion or afully-circumferential lesion at a single longitudinal segment or zone ofthe vessel. During treatment, the therapeutic element(s) 26 or 38 can beconfigured for partial or full occlusion of a vessel. Partial occlusioncan be useful, for example, to reduce ischemia, while full occlusion canbe useful, for example, to reduce interference (e.g., warming orcooling) caused by blood flow through the treatment location. In someembodiments, the therapeutic element(s) 26 or 38 can be configured tocause therapeutically-effective neuromodulation (e.g., using ultrasoundenergy) without contacting a vessel wall.

A variety of other suitable treatment locations are also possible in andaround the target artery, the target vein, and/or other suitablestructures. In a specific example, since the testicular artery 32becomes narrower and more tortuous further from the aorta, it can bemore convenient in some cases to treat the testicular artery 32 at itstrunk. Furthermore, a treatment procedure can include treatment at anysuitable number of treatment locations, e.g., a single treatmentlocation, two treatment locations, or more than two treatment locations.In some embodiments, different treatment locations can correspond todifferent portions of the target artery, the target vein, and/or othersuitable structures proximate tissue having relatively highconcentrations of targeted sympathetic nerves (e.g., afferent nervefibers associated with a diseased or damaged organ). The shaft(s) 24 or36 can be steerable (e.g., via one or more pull wires, a steerable guideor sheath catheter, etc.) and can be configured to move the therapeuticelement(s) 26 or 38 between treatment locations. At each treatmentlocation, the therapeutic element(s) 26 or 38 can be activated to causemodulation of nerves proximate the treatment location. Activating thetherapeutic element(s) 26 or 38 can include, for example, heating,cooling, stimulating, or applying another suitable treatment modality atthe treatment location. Activating the therapeutic element(s) 26 or 38can further include applying various energy modalities at varying powerlevels, intensities and for various durations for achieving modulationof nerves proximate the treatment location. In some embodiments, powerlevels, intensities and/or treatment duration can be determined andemployed using various algorithms for ensuring modulation of nerves atselect distances (e.g., depths) away from the treatment location.Furthermore, as noted previously, in some embodiments, the therapeuticelement(s) 26 or 38 can be configured to introduce (e.g., inject) achemical (e.g., a drug or other agent) into target tissue at thetreatment location. Such chemicals or agents can be applied at variousconcentrations depending on treatment location and the relative depth ofthe target nerves.

The therapeutic element(s) 26 or 38 can be positioned at a treatmentlocation within the target artery, for example, via a catheterizationpath including a femoral artery and the aorta, a catheterization pathincluding the internal iliac artery, the external iliac artery or anyvascular branches from these arteries, or another suitablecatheterization path, e.g., a radial or brachial catheterization path.Catheterization can be guided, for example, using imaging, e.g.,magnetic resonance, computed tomography, fluoroscopy, ultrasound,intravascular ultrasound, optical coherence tomography, or anothersuitable imaging modality. The therapeutic element(s) 26 or 38 can beconfigured to accommodate the anatomy of the target artery, the targetvein, and/or another suitable structure. For example, the therapeuticelement(s) 26 or 38 can include a balloon (not shown) configured toinflate to a size generally corresponding to the internal size of thetarget artery, the target vein, and/or another suitable structure. Insome embodiments, the therapeutic element(s) 26 or 38 can be animplantable device and a treatment procedure can include locating thetherapeutic element(s) 26 or 38 at the treatment location using theshaft(s) 24 or 36, fixing the therapeutic element(s) 26 or 38 at thetreatment location, separating the therapeutic element(s) 26 or 38 fromthe shaft(s) 24 or 36, and withdrawing the shaft(s) 24 or 36. Othertreatment procedures for modulation of sympathetic nerves in accordancewith embodiments of the present technology are also possible. Forexample, in some embodiments, a non-ablative and/or non-neuromodulatingamount of energy could be applied to simulate or re-create a patient'spain symptoms thereby allowing treating clinicians to beneficiallyposition the device prior to delivering modulating energy. In anotherembodiment, nerve signals can be temporarily blocked prior to deliveryof neuromodulating energy using, for example, anesthetic drugs,electrical overdrive pacing to exhaust nerve signals, etc., totemporarily abolish or diminish the pain sensation in order to determineif the device is positioned correctly.

FIG. 8 is a block diagram illustrating a method 800 of modulatingsympathetic nerves using the system 100 described above with referenceto FIGS. 2A-5 and 7. With reference to FIGS. 2A-5, 7, and 8 together,the method 800 can optionally include determining the location of painin a patient (if not yet determined) and/or selecting a suitable patientfor performing neuromodulation (block 802). The method 800 can includeintravascularly locating the neuromodulation assembly 110 in a deliverystate (e.g., low-profile configuration) at a first target site in ornear a target blood vessel (e.g., a celiac artery, superior mesentericartery or vein, a testicular artery or vein, a common iliac artery orvein, an internal iliac artery or vein, an external iliac artery orvein, an internal pudendal artery or vein, a superior gluteal artery orvein, deep circumflex iliac artery or vein, a vaginal artery or vein, auterine artery or vein and/or another suitable structure) (block 805).The treatment device 102 and/or portions thereof (e.g., theneuromodulation assembly 110) can be inserted into a guide catheter orsheath to facilitate intravascular delivery of the neuromodulationassembly 110. In certain embodiments, for example, the treatment device102 can be configured to fit within an 8 Fr guide catheter or smaller(e.g., 7 Fr, 6 Fr, etc.) to access small peripheral vessels. A guidewire (not shown), if present, can be used to manipulate and enhancecontrol of the shaft 112 and the neuromodulation assembly 110 (e.g., inan over-the-wire or a rapid-exchange configuration). In someembodiments, radiopaque markers and/or markings on the treatment device102 and/or the guide wire can facilitate placement of theneuromodulation assembly 110 at the target site (e.g., a target vesselof a patient with chronic pain). In some embodiments, a contrastmaterial can be delivered distally beyond the neuromodulation assembly110, and fluoroscopy and/or other suitable imaging techniques can beused to aid in placement of the neuromodulation assembly 110 at thetarget site.

The method 800 can further include connecting the treatment device 102to the console 104 (block 810), and determining whether theneuromodulation assembly 110 is in the correct position at the targetsite and/or whether the neuromodulation assembly (e.g., electrodes orcryotherapy balloon) is functioning properly (block 815). Once theneuromodulation assembly 110 is properly located at the target site andno malfunctions are detected, the console 104 can be manipulated toinitiate application of an energy field to the target site to causeelectrically-induced and/or thermally-induced modulation of targetsympathetic nerves near the target vessel (e.g., using electrodes orcryotherapeutic devices). Accordingly, heating and/or cooling of theneuromodulation assembly 110 causes modulation of sympathetic nerves(e.g., afferent nerve fibers transmitting pain signals) at the targetsite to reduce or diminish pain transmitting signals via sympatheticnerve fibers associated with the target site (block 820).

In one example, the treatment device 102 can be an RF energy emittingdevice and RF energy can be delivered through energy delivery elementsor electrodes to one or more locations along the inner wall of thetarget vessel for predetermined periods of time (e.g., 120 seconds). Insome embodiments, multiple treatments (e.g., 4-6) may be administered inmultiple target vessel locations to achieve a desired coverage. Forexample, the target vessel can be a first target vessel (e.g., a firsttesticular artery) and the treatment procedure can include modulatingnerves associated with a second target vessel (e.g., a second testicularartery) for the treatment of pain associated with the testes. In anotherexample, pain associated with conditions of the pancreas (e.g.,pancreatitis, pancreatic cancer) can include modulating nerves (e.g.,celiac plexus) associated with a first target vessel (e.g., a celiacartery) and can include modulating nerves (e.g., superior mesentericplexus) associated with a second target vessel (e.g., a superiormesenteric artery).

An objective of a treatment may be, for example, to heat tissue to adesired depth (e.g., at least about 3 mm) to a temperature (e.g., about65° C.) that would modulate one or more nerve fibers associated with oradjacent to one or more lesions formed in the vessel wall. A clinicalobjective of the procedure typically is to neuromodulate a sufficientnumber of sympathetic nerves (e.g., afferent nerves) to reduce ordiminish pain transmitting signals and/or to cause a reduction insympathetic tone or drive to the organ(s) without, for example,disrupting organ function and while minimizing vessel trauma. If theobjective of a treatment is met (e.g., tissue is heated to about 65° C.to a depth of about 3 mm) the probability of modulating nerve tissue(e.g., altering nerve function) is high. In some embodiments, a singleneuromodulation treatment procedure can provide for sufficientmodulation of target sympathetic nerves (e.g., modulation of asufficient number of nerve fibers) to provide a desired clinicaloutcome. In other embodiments, more than one treatment may be beneficialfor modulating a desired number or volume of target sympathetic nervefibers, and thereby achieve clinical success. The greater the number oftechnically successful treatments, the greater the probability ofmodulating a sufficient proportion of target sympathetic nerves, andthus the greater the probability of clinical success. In otherembodiments, an objective may include reducing or eliminating targetsympathetic nerve function completely.

In a specific example of using RF energy for sympathetic nervemodulation, a clinician can commence treatment which causes the controlalgorithm 122 (FIG. 7) to initiate instructions to the generator (notshown) to gradually adjust its power output to a first power level(e.g., 5 watts) over a first time period (e.g., 15 seconds). The powerincrease during the first time period is generally linear. As a result,the generator increases its power output at a generally constant rate ofpower/time, i.e., in a linear manner. Alternatively, the power increasemay be non-linear (e.g., exponential or parabolic) with a variable rateof increase. Once the first power level and the first time are achieved,the algorithm may hold at the first power level until a secondpredetermined period of time has elapsed (e.g., 3 seconds). At theconclusion of the second period of time, power is again increased by apredetermined increment (e.g., 1 watt) to a second power level over athird predetermined period of time (e.g., 1 second). This power ramp inpredetermined increments of about 1 watt over predetermined periods oftime may continue until a maximum power P_(MAX) is achieved or someother condition is satisfied. In one embodiment, P_(MAX) is 8 watts. Inanother embodiment, P_(MAX) is 10 watts, or in a further embodiment,P_(MAX) is 6.5 watts. In some embodiments, P_(MAX) can be about 6 wattsto about 10 watts. Optionally, the power may be maintained at themaximum power P_(MAX) for a desired period of time or up to the desiredtotal treatment time (e.g., up to about 120 seconds) or until aspecified temperature is reached or maintained for a specified timeperiod.

In another specific example, the treatment device 102 can be a cryogenicdevice and cryogenic cooling can be applied for one or more cycles(e.g., for 30 second increments, 60 second increments, 90 secondincrements, etc.) in one or more locations along the circumferenceand/or length of the target vessel. The cooling cycles can be, forexample, fixed periods or can be fully or partially dependent ondetected temperatures (e.g., temperatures detected by a thermocouple(not shown) of the neuromodulation assembly 110). In some embodiments, afirst stage can include cooling tissue until a first target temperatureis reached. A second stage can include maintaining cooling for a setperiod, such as 15-180 seconds (e.g., 90 seconds). A third stage caninclude terminating or decreasing cooling to allow the tissue to warm toa second target temperature higher than the first target temperature. Afourth stage can include continuing to allow the tissue to warm for aset period, such as 10-120 seconds (e.g., 60 seconds). A fifth stage caninclude cooling the tissue until the first target temperature (or adifferent target temperature) is reached. A sixth stage can includemaintaining cooling for a set period, such as 15-180 seconds (e.g., 90seconds). A seventh stage can, for example, include allowing the tissueto warm completely (e.g., to reach a body temperature).

After providing the therapeutically-effective neuromodulation energy(e.g., cryogenic cooling, RF energy, ultrasound energy, direct heat,etc.), the method 800 may also include determining whether theneuromodulation therapeutically treated the patient for management ofpain or otherwise sufficiently modulated nerves or other neuralstructures proximate the target site(s) for reducing pain (block 825).For example, the process of determining whether the neuromodulationtherapeutically treated the nerves can include determining whethernerves were sufficiently modulated or otherwise disrupted to reduce,suppress, inhibit, block or otherwise affect the afferent and/orefferent signals, such as pain signals (e.g., by evaluation of suitablebiomarkers, stimulation and recording of nerve signals, etc.). In afurther embodiment, patient assessment could be performed at timeintervals (e.g., 1 month, 3 months, 6 months, 12 months) followingneuromodulation treatment. For example, the patient can be assessed formeasurements of perceived pain using one or more pain measurement scales(FIGS. 1A-1E), and measures of sympathetic activity (e.g., MSNA, and/ornorepinephrine spillover to plasma, whole body norepinephrine spillover,and heart rate variability).

In other embodiments, various steps in the method 800 can be modified,omitted, and/or additional steps may be added. In further embodiments,the method 800 can have a delay between applyingtherapeutically-effective neuromodulation energy at a first target siteat or near a first target vessel and applying therapeutically-effectiveneuromodulation energy at a second target site at or near a secondtarget vessel. For example, neuromodulation of the first testicularartery can take place at a first treatment session, and neuromodulationof the second testicular artery can take place a second treatmentsession at a later time.

As discussed previously, treatment procedures for modulation ofsympathetic nerves in accordance with embodiments of the presenttechnology are expected to improve at least one aspect associated withperceived pain (e.g., pain caused by disease or damage to an abdominalor reproductive organ). For example, with respect to chronic painassociated with the abdominal or reproductive viscera, modulation ofsympathetic nerves at an appropriate target vessel as disclosed hereinand in accordance with embodiments of the present technology is expectedto reduce a perceived intensity of pain, change a quality of pain, orincrease physical or mental function/ability of a patient experiencingpain. In a particular example, the intensity level of pain in a patientis expected to be reduced at least about 5% within about three monthsafter modulating the sympathetic nerves associated with the damaged ordiseased organ in the patient that is believed to be the cause of thepain. These and other clinical effects are expected to be detectableimmediately after a treatment procedure or after a delay, e.g., of 1, 2,or 3 months. In some instances, it may be useful to repeatneuromodulation at the same treatment location or a different treatmentlocation after a suitable delay, e.g., 1, 2, or 3 years. In still otherembodiments, however, other suitable treatment regimens or techniquesmay be used.

IX. PERTINENT ANATOMY AND PHYSIOLOGY

The following discussion provides further details regarding pertinentpatient anatomy and physiology. This section is intended to supplementand expand upon the previous discussion regarding the relevant anatomyand physiology, and to provide additional context regarding thedisclosed technology and the therapeutic benefits associated withneuromodulation for the treatment and management of pain associated withthe abdominal and/or reproductive viscera.

A. The Sympathetic Nervous System

The SNS is a branch of the autonomic nervous system along with theenteric nervous system and parasympathetic nervous system. It is alwaysactive at a basal level (called sympathetic tone) and becomes moreactive during times of stress. Like other parts of the nervous system,the SNS operates through a series of interconnected neurons. Sympatheticneurons are frequently considered part of the peripheral nervous system(PNS), although many lie within the central nervous system (CNS).Sympathetic neurons of the spinal cord (which is part of the CNS)communicate with peripheral sympathetic neurons via a series ofsympathetic ganglia. Within the ganglia, spinal cord sympathetic neuronsjoin peripheral sympathetic neurons through synapses. Spinal cordsympathetic neurons are therefore called presynaptic (or preganglionic)neurons, while peripheral sympathetic neurons are called postsynaptic(or postganglionic) neurons.

At synapses within the sympathetic ganglia, preganglionic sympatheticneurons release acetylcholine, a chemical messenger that binds andactivates nicotinic acetylcholine receptors on postganglionic neurons.In response to this stimulus, postganglionic neurons principally releasenoradrenaline (norepinephrine). Prolonged activation may elicit therelease of adrenaline from the adrenal medulla.

Once released, norepinephrine binds adrenergic receptors on peripheraltissues. Binding to adrenergic receptors causes a neuronal and hormonalresponse. The physiologic manifestations include pupil dilation,increased heart rate, occasional vomiting, and increased blood pressure.Increased sweating is also seen due to binding of cholinergic receptorsof the sweat glands.

The SNS is responsible for up- and down-regulation of many homeostaticmechanisms in living organisms. Fibers from the SNS innervate tissues inalmost every organ system, providing at least some regulatory functionto physiological features as diverse as pupil diameter, gut motility,and urinary output. This response is also known as the sympatho-adrenalresponse of the body, as the preganglionic sympathetic fibers that endin the adrenal medulla (but also all other sympathetic fibers) secreteacetylcholine, which activates the secretion of adrenaline (epinephrine)and to a lesser extent noradrenaline (norepinephrine). Therefore, thisresponse that acts primarily on the cardiovascular system is mediateddirectly via impulses transmitted through the SNS and indirectly viacatecholamines secreted from the adrenal medulla.

Science typically looks at the SNS as an automatic regulation system,that is, one that operates without the intervention of consciousthought. Some evolutionary theorists suggest that the SNS operated inearly organisms to maintain survival as the SNS is responsible forpriming the body for action. One example of this priming is in themoments before waking, in which sympathetic outflow spontaneouslyincreases in preparation for action.

1. The Sympathetic Chain

As shown in FIG. 9, the SNS provides a network of nerves that allows thebrain to communicate with the body. Sympathetic nerves originate insidethe vertebral column, toward the middle of the spinal cord in theintermediolateral cell column (or lateral horn), beginning at the firstthoracic segment of the spinal cord and are thought to extend to thesecond or third lumbar segments. Because its cells begin in the thoracicand lumbar regions of the spinal cord, the SNS is said to have athoracolumbar outflow. Axons of these nerves leave the spinal cordthrough the anterior rootlet/root. They pass near the spinal (sensory)ganglion, where they enter the anterior rami of the spinal nerves.However, unlike somatic innervation, they quickly separate out throughwhite rami connectors that connect to either the paravertebral (whichlie near the vertebral column) or prevertebral (which lie near theaortic bifurcation) ganglia extending alongside the spinal column.

In order to reach the target organs and glands, the axons travel longdistances in the body. Many axons relay their message to a second cellthrough synaptic transmission. The first cell (the presynaptic cell)sends a neurotransmitter across the synaptic cleft (the space betweenthe axon terminal of the first cell and the dendrite of the second cell)where it activates the second cell (the postsynaptic cell). The messageis then propagated to the final destination.

In the SNS and other neuronal networks of the peripheral nervous system,these synapses are located at sites called ganglia, discussed above. Thecell that sends its fiber to a ganglion is called a preganglionic cell,while the cell whose fiber leaves the ganglion is called apostganglionic cell. As mentioned previously, the preganglionic cells ofthe SNS are located between the first thoracic (T1) segment and thirdlumbar (L3) segments of the spinal cord. Postganglionic cells have theircell bodies in the ganglia and send their axons to target organs orglands. The ganglia include not just the sympathetic trunks but also thecervical ganglia (superior, middle and inferior), which sendssympathetic nerve fibers to the head and thorax organs, and the celiacand mesenteric ganglia (which send sympathetic fibers to the gut).

2. Organ Innervation

The abdominal organs are innervated by the celiac plexus and thesuperior mesenteric plexus or ganglion (FIGS. 2A and 2B), a network ofnerve fibers accompanying the abdominal vessels. The celiac ganglion,aorticorenal ganglion, the phrenic plexus, the hepatic plexus, theinferior gastric plexus, the lineal plexus, the superior gastric plexus,the suprarenal plexus, the renal plexus, the spermatic plexus, thesuperior mesenteric plexus, the abdominal aortic plexus, and theinferior mesenteric plexus are all subsidiaries of the celiac plexus andprovide innervation to much of the abdominal and reproductive viscera.The pelvis plexuses supply the viscera the pelvic cavity (e.g., theuterine plexus, the vaginal plexus).

3. Sympathetic Neural Activity

Messages travel through the SNS in a bidirectional flow. Efferentmessages may trigger changes in different parts of the bodysimultaneously. For example, the SNS may accelerate heart rate; widenbronchial passages; decrease motility (movement) of the large intestine;constrict blood vessels; increase peristalsis in the esophagus; causepupil dilation, cause piloerection (i.e., goose bumps), causeperspiration (i.e., sweating), and raise blood pressure. Afferentmessages carry signals from various organs and sensory receptors in thebody to other organs and, particularly, the brain.

Hypertension, heart failure and chronic kidney disease are a few of manydisease states that result from chronic activation of the SNS,especially the renal sympathetic nervous system. Chronic activation ofthe SNS is a maladaptive response that drives the progression of thesedisease states. Pharmaceutical management of therenin-angiotensin-aldosterone system (RAAS) has been a longstanding, butsomewhat ineffective, approach for reducing overactivity of the SNS.

As mentioned above, the sympathetic nerve fibers, and in particular, theafferent nerve fibers carry and/or transmit pain signals fromnociceptors (e.g., pain receptors) in a damaged or diseased organ (e.g.,pancreas, liver, testes, vulva, etc.) or body structure (e.g., pelvis)via the pelvis plexus network or the celiac plexus network and to thespinal cord and then to the thalamus and cortex of the brain, therebyinducing the sensation of pain. Typically, nociceptive pain is caused bystimulation of these sympathetic nerve fibers only when a thresholdintensity (e.g., a harmful intensity) is achieved within the tissue.

X. FURTHER EXAMPLES

1. A method of treating a human patient having chronic pain associatedwith a disease or condition of a pancreas, liver, biliary tract,gallbladder, spleen, stomach, small intestine colon or of an abdominalvisceral artery, the method comprising:

-   -   intravascularly positioning a neuromodulation assembly within a        target blood vessel of the patient and adjacent to a target        sympathetic nerve of the patient; and    -   reducing sympathetic neural activity in the patient by        delivering energy to the target sympathetic nerve via the        neuromodulation assembly to modulate a function of the target        sympathetic nerve,    -   wherein reducing sympathetic neural activity improves a        perceived pain associated with the disease or condition of the        patient.

2. A method of treating a human patient having chronic pain associatedwith a disease or condition of the reproductive system, the methodcomprising:

-   -   intravascularly positioning a neuromodulation assembly within a        target blood vessel of the patient and adjacent to a target        sympathetic nerve of the reproductive system of the patient; and    -   reducing sympathetic neural activity in the patient by        delivering energy to the target sympathetic nerve via the        neuromodulation assembly to modulate a function of the target        sympathetic nerve,    -   wherein reducing sympathetic neural activity improves a        perceived pain associated with the disease or condition of the        patient.

3. The method of example 1 or example 2 wherein reducing sympatheticneural activity in the patient in a manner that improves a perceivedpain by the patient comprises reducing a level of pain as reported on apain scale.

4. The method of example 3 wherein the pain scale is a standardizedVisual Analog Scale (VAS), and wherein a post-neuromodulation VAS scoreof the patient is less than a pre-neuromodulation VAS score of thepatient.

5. The method of example 3 wherein the pain scale is at least one of astandardized Visual Analog Scale, a graphic faces pain scale, aWong-Baker FACES Pain Rating Scale, a colored analogue scale, a FaceLegs Arms Cry Consolability Scale, a word descriptor scale, a verbalscale and a functional pain scale.

6. The method of any one of examples 1-5 wherein reducing sympatheticneural activity improves a perceived pain by the patient by at leastabout 5%.

7. The method of any one of examples 1-6 wherein reducing sympatheticneural activity improves a perceived pain by the patient by at leastabout 20% within about three months to about 12 months after reducingsympathetic neural activity in the patient by delivering energy to thetarget sympathetic nerve.

8. The method of any one of examples 1-7 wherein reducing sympatheticneural activity improves at least one of a perceived pain intensitylevel, a quality of pain, a level of physical function of the patient,and a level of mental function of the patient.

9. The method of any one of examples 1 or 3-8 wherein the chronic painis associated with a disease or condition comprising pancreatitis orpancreatic cancer.

10. The method of any one of examples or 3-9 wherein intravascularlypositioning a neuromodulation assembly within a target blood vessel ofthe patient includes positioning a neuromodulation assembly within aceliac artery.

11. The method of any one of examples or 3-10 wherein intravascularlypositioning a neuromodulation assembly within a target blood vessel ofthe patient includes positioning a neuromodulation assembly within asuperior mesenteric artery.

12. The method of any one of examples 2-8 wherein the chronic pain isassociated with a testicle of the patient.

13. The method of any one of examples 2-8 or 12 wherein intravascularlypositioning a neuromodulation assembly within a target blood vessel ofthe patient includes positioning a neuromodulation assembly within atesticular artery.

14. The method of any one of examples 2-8, 12, or 13 wherein the targetsympathetic nerve is a testicular afferent nerve.

15. The method of any one of examples 2-8 wherein the chronic pain isassociated with the vulva, vagina and/or clitoris.

16. The method of any one of examples 2-8 or 12-15 whereinintravascularly positioning a neuromodulation assembly within a targetblood vessel of the patient includes positioning a neuromodulationassembly within an external iliac artery, an interior iliac artery, oran internal pudendal artery.

17. The method of example 15 wherein the target sympathetic nerveresides in the vaginal plexus, and wherein intravascularly positioning aneuromodulation assembly within a target blood vessel of the patientincludes positioning a neuromodulation assembly within a vaginal artery.

18. The method of any one of examples 1-17 wherein reducing sympatheticneural activity in the patient by delivering energy to the targetsympathetic nerve comprises at least partially inhibiting afferentneural activity.

19. The method of any one of examples 1-18 wherein reducing sympatheticneural activity in the patient by delivering energy to the targetsympathetic nerve comprises thermally inducing modulation of the targetsympathetic nerve of the patient via an intravascularly positionedcatheter carrying one or more thermal energy delivery elementspositioned at least proximate to the target sympathetic nerve.

20. The method of example 19 wherein modulating the target sympatheticnerve includes heating the target sympathetic nerve from within thetarget blood vessel of the patient via the one or more thermal energydelivery elements.

21. The method of example 20 wherein thermally modulating the targetsympathetic nerve includes cryotherapeutically cooling the targetsympathetic nerve via the one or more thermal energy delivery elements.

22. The method of example 20 wherein thermally modulating the targetsympathetic nerve includes delivering ultrasound energy to the targetsympathetic nerve.

23. The method of any one of examples 1 or 3-8 wherein the chronic painis associated with visceral artery insufficiency.

24. The method of any one of examples 1 or 3-8 wherein the chronic painis associated with a hepatobiliary disease.

25. A method, comprising:

-   -   percutaneously introducing a neuromodulation assembly at a        distal portion of a treatment device proximate to neural fibers        innervating a damaged or diseased organ of a human patient        diagnosed with chronic or debilitating pain, wherein the damaged        or diseased organ comprises at least one of a pancreas, liver,        biliary tract, gallbladder, spleen, stomach, small intestine,        colon or a reproductive organ;    -   partially disrupting function of at least afferent neural fibers        innervating the organ by applying thermal energy to the neural        fibers via the neuromodulation assembly; and    -   removing the neuromodulation assembly from the patient after        treatment,    -   wherein partial disruption of the function of at least the        afferent neural fibers innervating the organ therapeutically        treats the chronic or debilitating pain.

26. The method of example 25 wherein the patient is diagnosed with adisease of the pancreas, and wherein partial disruption of the functionof at least the afferent neural fibers innervating the pancreas reducesa perceived pain level by at least about 10% in the patient.

27. The method of example 25 or example 26 wherein the neural fibersoriginate from the celiac plexus or the superior mesenteric plexus.

28. The method of example 25 wherein the patient is diagnosed withorchialgia, and wherein partial disruption of the function of at leastthe afferent neural fibers innervating a testicle reduces a perceivedpain level by at least about 10% in the patient.

29. The method of example 25 or example 28 wherein the neural fibersoriginate from the spermatic plexus, the lumbar plexus or the sacralplexus.

30. A method for managing pain in a human patient, the methodcomprising:

-   -   transluminally positioning an energy delivery element of a        catheter within a target blood vessel of the patient and        adjacent to neural fibers that innervate a damaged or diseased        pancreas, liver, biliary tract, gallbladder, spleen, stomach,        small intestine, colon, abdominal visceral artery, or        reproductive organ of the patient; and    -   at least partially ablating the neural fibers innervating the        organ of the patient via the energy delivery element,    -   wherein at least partially ablating the neural fibers        innervating the organ results in a therapeutically beneficial        improvement in a measurable parameter associated with the pain        of the patient.

31. The method of example 30, further comprising administering one ormore pharmaceutical drugs to the patient, wherein the pharmaceuticaldrugs are selected from the group consisting of analgesics,anti-inflammatory drugs and/or anti-depressants.

32. The method of example 30 or example 31 wherein at least partiallyablating the neural fibers innervating the organ of the patient via theenergy delivery element comprises delivering a thermal electric field tothe neural fibers via at least one electrode.

XI. CONCLUSION

The above detailed descriptions of embodiments of the technology are notintended to be exhaustive or to limit the technology to the precise formdisclosed above. Although specific embodiments of, and examples for, thetechnology are described above for illustrative purposes, variousequivalent modifications are possible within the scope of thetechnology, as those skilled in the relevant art will recognize. Forexample, while steps are presented in a given order, alternativeembodiments may perform steps in a different order. Further, inadditional embodiments, the system 100 may include a treatment deviceconfigured to deliver therapeutic energy to the patient from an externallocation outside the patient's body, i.e., without direct or closecontact to the target site. The various embodiments described herein mayalso be combined to provide further embodiments.

From the foregoing, it will be appreciated that specific embodiments ofthe technology have been described herein for purposes of illustration,but well-known structures and functions have not been shown or describedin detail to avoid unnecessarily obscuring the description of theembodiments of the technology. Where the context permits, singular orplural terms may also include the plural or singular term, respectively.

Moreover, unless the word “or” is expressly limited to mean only asingle item exclusive from the other items in reference to a list of twoor more items, then the use of “or” in such a list is to be interpretedas including (a) any single item in the list, (b) all of the items inthe list, or (c) any combination of the items in the list. Additionally,the term “comprising” is used throughout to mean including at least therecited feature(s) such that any greater number of the same featureand/or additional types of other features are not precluded. It willalso be appreciated that specific embodiments have been described hereinfor purposes of illustration, but that various modifications may be madewithout deviating from the technology. Further, while advantagesassociated with certain embodiments of the technology have beendescribed in the context of those embodiments, other embodiments mayalso exhibit such advantages, and not all embodiments need necessarilyexhibit such advantages to fall within the scope of the technology.Accordingly, the disclosure and associated technology can encompassother embodiments not expressly shown or described herein.

We claim:
 1. A method for reducing a pain level in a patient,comprising: measuring a baseline condition of a pain parameterassociated with a diagnosed disease or condition in the patient;intravascularly positioning a neuromodulation assembly within a targetblood vessel of the patient and adjacent to a target sympathetic nerveof the patient; at least partially ablating the target sympathetic nerveusing the neuromodulation assembly; measuring a post-neuromodulationcondition of the pain parameter; and comparing the post-neuromodulationcondition to the baseline condition to determine a change in the painparameter, the change in the pain parameter providing a measurableindicator of a reduction of the pain level in the patient followingtreatment using the neuromodulation assembly.
 2. The method of claim 1,wherein the pain parameter is at least one of pain severity, painquality, pain radiation pattern, pain duration, degree of pain levelfluctuation, frequency of pain remissions, or level of function of thepatient diagnosed with chronic pain.
 3. The method of claim 1, furthercomprising: removing the neuromodulation assembly from the patient afterat least partially ablating the target sympathetic nerve.
 4. The methodof claim 1, wherein at least partially ablating the target sympatheticnerve using the neuromodulation assembly includes delivering energy tothe target sympathetic nerve.
 5. The method of claim 4, wherein thedelivered energy includes one of radio frequency energy, pulsed radiofrequency energy, microwave energy, optical energy, ultrasound energy,cryotherapeutic energy, directed heat energy, chemicals, radiation orcombinations thereof.
 6. The method of claim 1, wherein the pain levelis associated with a diagnosed disease or condition of a pancreas,liver, biliary tract, gallbladder, spleen, stomach, small intestine,color or of an abdominal visceral artery.
 7. The method of claim 1,wherein the pain parameter is at least one of pain severity, painquality, pain radiation pattern, pain duration, a degree of pain levelfluctuation, frequency of pain remissions, or level of function of thepatient diagnosed with chronic pain.
 8. The method of claim 1, furthercomprising: assessing the baseline condition and thepost-neuromodulation condition of the pain parameter in the patientusing a pain scale.
 9. The method of claim 1, wherein the change in thepain parameter is a decrease in sympathetic nerve activity over 1 month,2 months, 3 months, 6 months, 9 months or 12 monthspost-neuromodulation.
 10. A method for reducing a pain level in apatient, comprising: measuring a baseline condition of a pain parameterassociated with a diagnosed disease or condition in the patient, thepain parameter being at least one of pain severity, pain quality, painradiation pattern, pain duration, degree of pain level fluctuation,frequency of pain remissions, or level of function of the patientdiagnosed with chronic pain; intravascularly positioning aneuromodulation assembly within a target blood vessel of the patient andadjacent to a target sympathetic nerve of the patient; at leastpartially ablating the target sympathetic nerve using theneuromodulation assembly; measuring a post-neuromodulation condition ofthe pain parameter; and comparing the post-neuromodulation condition tothe baseline condition to determine a change in the pain parameter, thechange in the pain parameter providing a measurable indicator of areduction of the pain level in the patient following treatment using theneuromodulation assembly.
 11. The method of claim 10, furthercomprising: removing the neuromodulation assembly from the patient afterat least partially ablating the target sympathetic nerve.
 12. The methodof claim 10, wherein at least partially ablating the target sympatheticnerve using the neuromodulation assembly includes delivering energy tothe target sympathetic nerve.
 13. The method of claim 12, wherein thedelivered energy includes one of radio frequency energy, pulsed radiofrequency energy, microwave energy, optical energy, ultrasound energy,cryotherapeutic energy, directed heat energy, chemicals, radiation orcombinations thereof.
 14. The method of claim 10, wherein at leastpartially ablating the target sympathetic nerve changes thepost-neuromodulation condition measurement by at least 5% as compared tothe baseline condition measurement.
 15. The method of claim 10, whereinat least partially ablating the target sympathetic nerve changes thepost-neuromodulation condition measurement by at least 20% as comparedto the baseline condition measurement within three months to 12 monthsfollowing the treatment and removal of the neuromodulation assembly fromthe patient.
 16. The method of claim 10, wherein the pain level isassociated with a diagnosed disease or condition of a pancreas, liver,biliary tract, gallbladder, spleen, stomach, small intestine, color orof an abdominal visceral artery.
 17. The method of claim 10, furthercomprising: assessing the baseline condition and thepost-neuromodulation condition of the pain parameter in the patientusing a pain scale.
 18. A method for reducing a pain level in a patient,comprising: measuring a baseline condition of a pain parameterassociated with a diagnosed disease or condition in the patient;intravascularly positioning a neuromodulation assembly within a targetblood vessel of the patient and adjacent to a target sympathetic nerveof the patient; at least partially ablating the target sympathetic nerveby delivering energy to the target sympathetic nerve via theneuromodulation assembly; measuring a post-neuromodulation condition ofthe pain parameter; and comparing the post-neuromodulation condition tothe baseline condition to determine a change in the pain parameter, thechange in the pain parameter providing a measurable indicator of areduction of the pain level in the patient following treatment using theneuromodulation assembly.
 19. The method of claim 18, wherein the painparameter is at least one of pain severity, pain quality, pain radiationpattern, pain duration, degree of pain level fluctuation, frequency ofpain remissions, or level of function of the patient diagnosed withchronic pain.
 20. The method of claim 18, further comprising: removingthe neuromodulation assembly from the patient after at least partiallyablating the target sympathetic nerve.